BOOKS BY DR. FISCHER 



PUBLISHED BY 

JOHN WILEY & SONS, Inc. 



The Physiology of Alimentation. 

viii + 348 pages. 51 by 8. 30 figures. Cloth. 
S2.00 net. 

Fats and Fatty Degeneration. 

A Physico-Chemical Study of Emulsions 
and the Normal and Abnormal Distribution 
of Fat in Protoplasm. (With Dr. Marian 
O. Hooker.) viii + 155 pages. 6 by 9. 65 
figures. Cloth. $2.00 net. 

Oedema and Nephritis. 

A Critical, Experimental and Clinical Study 
of the Physiology and Pathology of Water 
Absorption in the Living Organism. Third 
and Enlarged Edition. xvi+ 922 pages. 6 by 9. 
217 figures. Cloth. $10.00 net. 

Soaps and Proteins. 

Their Colloid Chemistry in Theory and Prac- 
tice. (With George D. McLaughlin and 
Dr. Marian O. Hooker.) In preparation. 

TRANSLATIONS 
Physical Chemistry in the Service of Medicine. 

Seven Addresses by Dr. Wolfgang Patjli, 
Professor in the Biological Experiment 
Station in Vienna. Authorized Translation 
by Dr. Martin H. Fischer, ix + 156 pages. 
5 by 7|. Cloth. $1.25 net. 

An Introduction to Theoretical and Applied 
Colloid Chemistry. 

Five Lectures by Dr. Wolfgang Ostwald, 
Professor in the University of LeiDzig. 
Authorized Translation by Dr. Martin H. 
Fischer, xiv + 232 pages. 6 by 9. 45 figures. 
$2.50 net. 



(EDEMA AND NEPHRITIS 



A CRITICAL, EXPERIMENTAL AND CLINICAL STUDY 
OF THE PHYSIOLOGY AND PATHOLOGY OF 
WATER ABSORPTION IN THE 
LIVING ORGANISM 



BY 

MARTIN H, FISCHER 

Doctor of Medicine 
Eichberg Professor of Physiology in the University of Cincinnati 



THIRD AND ENLARGED EDITION 



NEW YORK 

JOHN WILEY & SONS, Inc. 
London: CHAPMAN & HALL, Limited 
1921 



Copyright, 1910, 1911, 1915, 1921 
BT 

MARTIN H. FISCHER 



FEB -3 1821 



g)C!,A608209 




TO 

C. R. F. 



Science commences when for a great num- 
ber of experiences one general conception is 
found which will embrace all cases. Thus, 
if you know that a certain remedy has cured 
Callias of a certain disease and the" same rem- 
edy has produced the same effect on Socrates 
and on several other persons, that is Expe- 
rience, but to know that a certain remedy will 
cure all persons attacked with the same dis- 
ease is Science. Experience is the knowl- 
edge of individual things. Science is that of 
Univer sals. —ARISTOTLE. 



PEEFACE TO THE THIED EDITION 



I do not deny that the call for a third edition gives me a sense of 
satisfaction. It means that the ideas here expressed have made 
their way among the open minded of my profession and this in 
spite of the fact that what is written in the succeeding pages has 
been almost universally condemned, even though rarely read 
through, by those clothed in the robes of authority. 

I have found it well in this edition, as in the second, to leave 
what was written in the first unaltered, except for typographical 
errors. The changes again consist in additions to the text, which 
in this volume comprise a more detailed development of the con- 
cept of the hydrophilic colloid, the insertion of observations on 
the swelling of aleuronat, the introduction of further experiments 
on the swelling and solution of gelatin in non-acid media, a dis- 
cussion of the nature, of the increase and decrease in hydration 
capacity of the proteins, a broader discussion of the essential nature 
of water secretion, experimental evidence for the importance of 
distinguishing between swelling and "solution" in colloids, new 
pages on the behavior of protein colloids in the presence of buffer 
mixtures, renewed emphasis on the non-relationship between 
disease of the kidney and the so-called signs, symptoms and com- 
plications of nephritis, additional suggestions regarding the treat- 
ment of nephritis and a bolder insistence upon the purely infectious 
origin of vascular disease with its consequences, including the 
chronic interstitial nephritis of Bright. I have also taken the 
liberty of adding in an appendix two articles, somewhat revised, 
dealing in the first instance with the monumental work of Frank 
Billings and his focal infections (of interest because this chapter 
reiterates the principles and practice to be followed in dealing 
clinically with infections in and about the teeth) and in the 
second with a clinical lecture on the classification and treatment 
of the nephritides. While the substance of each of these papers 

v 



VI 



PREFACE TO THE THIRD EDITION 



appeared even in the second edition, my friends have found the 
form of these papers particularly helpful, and since they are 
not readily available in their original places of publication they 
are reprinted here. 

The fact that the original text has not been changed but only 
added to, may prove of service to those workers in medicine who 
have any regard for the historical aspects of medical and biological 
science. It is an ironic fact that I can cite to-day as best proof for 
the correctness of the general notions for which I have pleaded 
for more than a decade the observations of the very workers who 
have been most violent in their criticism of what I have written. 
The colloid-chemical notions of water absorption by protoplasm 
with their many physiological and pathological corollaries, so 
long a jest, are now embodied by these workers in their scientific 
discussions as self-evident truths in which the original sponsor 
needs never to be mentioned. High commissions find alkali, 
glucose and colloid injection mixtures the chief things of service 
in shock ; surgeons suddenly discover that their bad operative risks 
are "acidosed" and that food and alkali may save them; while 
those who thought the acid content of the living mass an unchange- 
able value are running about their wards with respiration bags and 
hydrogen ion determinators. 

The fact that the cellular changes discussed in these pages and 
characteristic of disease are in essence changes in the colloid state 
of protoplasm has constituted an ever-present temptation to dis- 
cuss in greater detail the developments of pure colloid chemistry 
itself and its interesting theoretical deductions. I have, however, 
steered clear of all hypothesis so that this edition might remain, 
as the former ones, intensely practical. The nature of fatty degen- 
eration I have taken up in a volume which has preceded this one. 1 
The nature of the action of acids, alkalies and salts upon proto- 
plasm (together with a discussion of the intrinsic character of the 
changes thus brought about) is corollary to my observations on 
soaps, a volume covering which subject 2 I hope to have out of 
hand shortly. 

I cannot let this new edition go to print without acknowledg- 
ing my gratitude to various friends. I owe much to my secretary 

1 ''Fats and Fatty Degeneration," John Wiley and Sons, Inc., New York 
(1917). 

2 "Soaps and Proteins," John Wiley and Sons, Inc., New York. (In press.) 



PREFACE TO THE THIRD EDITION vii 

Doris Wulff. Renewed thanks are due Harry M. Levy, who 
has continued his generous support of the Joseph Eichberg 
Laboratory in spite of its seeming vagaries. For inspiration to 
scientific work and for example in perseverance and courage I have 
times without number turned to the builder of resurgent medical 
Cincinnati, Christian R. Holmes. 

Martin H. Fischer. 

University of Cincinnati, 
June, 1920. 



PREFACE TO THE SECOND EDITION 



These pages give in combined form the contents of the 
1909 Nathan Lewis Hatfield Prize Essay of the College of 
Physicians of Philadelphia, and of the 1911 Cartwright 
Prize Essay of the Alumni of the College of Physicians and 
Surgeons of Columbia University, New York, previously pub- 
lished as separate volumes bearing the titles " (Edema " and 
" Nephritis." The close association between the two made their 
appearance in combined form seem advisable. The chief 
changes which time has rendered necessary consist of additions 
to the general text embodying the results of later experimental 
and clinical observations in good part not readily accessible to 
English readers — the main argument remains as before. 

Throughout the text are mentioned those who with me did 
the day's work. These references to James J. Hogan, Edmund 
M. Baehr, Gertrude Moore, Marian 0. Hooker, Thomas 
H. Kelly, Hayward G. Thomas, William H. Strietmann, 
Anne Sykes and Carl Hiller but ill express my indebtedness 
to them. Nor would I fail to acknowledge the intelligent and 
faithful help of my technical assistant, Josef Kupka. In these 
paragraphs I can only record my keen appreciation of what 
they did. 

To Lauder W. Jones I have often turned for help in 
matters chemical, to Louis Trenchard More in matters 
physical. Alfred Brodbeck made possible the observations on 
athletes. Charles Goosman gave of his time and skill to pre- 
pare the photomicrographs. Charles Hecker and Peter 
Scherrer made many of the other photographs. To all these I 
would express my sincere thanks. 

The now old views restated and elaborated in this volume 
have not gone unchallenged. Where these challenges have 

ix 



X 



PREFACE TO THE SECOND EDITION 



sprung from scientific doubt it has not been difficult to reach 
common ground by discussion. Where the personal has entered 
into the spirit of the attack I have succeeded, in part at least, 
in keeping silent. As this is my wish for the future, will the 
interested reader of disputed points examine the evidence away 
from the noise of the pleading attorneys? 

Much of the older work and most of the newer in this volume 
was shaped in the Josefh Eichberg Laboratory of Physiology 
in the University of Cincinnati. The atmosphere prevailing 
there, which recognizes that the new is born as a minority point 
of view and hence is unpopular, and that the function of a 
university is to give it sanctuary, has been made possible by the 
generosity of Harry M. Levy. 

Martin H. Fischer. 

University of Cincinnati, 1914. 



TABLE OF CONTENTS 



PART ONE 
THE ARGUMENT 
(Pages 1-37) 



PART TWO 

ABSORPTION AND SECRETION IN INDIVIDUAL CELLS 
AND TISSUES 

PAGE 

I. The Problem 41 

II. The Absorption of Water by Colloids 44 

1. Remarks on Colloids: Nomenclature 44 

2. Observations on the Swelling of Fibrin 61 

3. Observations on the Swelling of Gelatin 75 

4. Observations on the Swelling of Gluten 129 

5. Observations on the Swelling of Aleuronat 133 

6. Hydration and Dehydration in Liquid Colloids 145 

7. On the Nature of the Increased and Decreased Hydration 

Capacity of the Proteins 148 

III. The Analogy between the Swelling of Certain Protein Colloids and 

the Swelling of Protoplasm 151 

1. The Analogy between the Absorption of Water by Certain 

Protein Colloids and by Muscle 152 

2. The Analogy between the Absorption of Water by Certain 

Protein Colloids and by the Eye 1 69 

3. The Analogy between the Absorption of Water by Certain 

Protein Colloids and by Nervous Tissue 178 

IV. The Biological Significance of the Analogy between the Absorption 

of Water by Certain Protein Colloids and the Absorption of 
Water by Different Tissues 193 

1. Introductory Remarks 193 

2. Criticism of the Osmotic Theory of Water Absorption by 

Protoplasm 195 

3. Criticism of the Lipoid Membrane Theory. . . 201 

4. Adequacy of the Colloid-chemical Theory of Absorption and 

Secretion 204 

5. Absorption and Secretion of Dissolved Substances by Proto- 

plasm 206 

xi 



xii 



TABLE OF CONTENTS 



PART THREE 
(EDEMA 

PAGE 

I. Introduction 217 

II. The Cause of (Edema Resides in the Tissues 220 

III. ' On the Nature and Cause of (Edema 232 

1. An Abnormal Production or Accumulation of Acids or 

Conditions Predisposing Thereto Exist in all States in which 
We Encounter (Edema 233 

2. Any Means by which an Abnormal Production or Accumula- 

tion of Acid in a Tissue May be Brought about is a Means 

of Producing an (Edema 243 

3. Those Conditions which are Capable of Decreasing the Hydra- 

tion of (Protein) Colloids Decrease (Edema, while Those Un- 
able to do so do not Affect It 249 

4. On (Edema Due to Other than Acid Causes 262 

IV. On the Passive Congestion (Edemas of the Kidney and the Liver 268 

V. On the Nature and Cause of Pulmonary (Edema 276 

VI. Syneresis and the Accumulation of Fluid in the Body Cavities in 

(Edema 283 

VII. Concluding Remarks ,,,,,, 285 



PART FOUR 

ABSORPTION AND SECRETION IN THE COMPLEX ORGANISM 

I. The General Problem 293 

II. On Absorption 296 

1. General Remarks on the Physico-chemical Structure of an 

Absorbing System in the Complex Organism , . . . . 296 

2. Absorption from the Peritoneal Cavity 299 

3. Absorption from the Castro-Intestinal Tract 311 

4. Historical and Critical Remarks on the Theory of Absorption. 

Peritoneal and Alimentary Absorption of Dissolved Sub- 
stances 315 

III. On Secretion 325 

1. Introduction 325 

2. General Remarks on the Structure of a Secreting System in 

the Complex Organism 326 

3. A Model Illustrating Some Phases of Urinary Secretion 327 

4. The Output of Water by the Kidney 330 

5. On the Colloid-chemical Action of the Diuretic Salts. How the 

Saline Diuretics Produce Diuresis 339 

6. On the Colloid-chemistry of Sugar Diuresis 349 



TABLE OF CONTENTS 



xiii 



7. Discussion of the Mechanism of Water Secretion by the 

Kidney. Some General Conditions Influencing Water 
Output. Diuretics of the Second Order.. - 357 

8. Historical and Critical Remarks on Urinary Secretion 362 

9. Transition from the Physiological to the Pathological in 

Kidney Function 365 

10. The Secretion of Dissolved Substances 367 

11. A Second Model Illustrating Some Phases of Kidney Secre- 

tion i 371 

12. A Third Model Illustrating Some Phases of Kidney Secretion . . 380 

13. Concluding Remarks on Absorption and Secretion. Lymph 

Formation. Vasomotor and Secretory Nerves 397 

IV. Maintenance of the Circulating Fluids in the Body 403 

1 . Why the Blood Remains in the Blood Vessels 403 

2. On the Treatment of Shock 415 

3. Critical Remarks on Shock 423 



PART FIVE 

THE COLLOID-CHEMICAL THEORY OF WATER ABSORPTION 
AND SOME PROBLEMS IN BIOLOGY, PHYSIOLOGY AND 
PATHOLOGY 



I. Turgor, Plasmolysis and Plasmoptysis 429 

II. On the Absorption of Water by Spermatozoa, Epithelial Cells and 

White Blood Corpuscles 430 

III. On the Interpretation of Some Experiments on Water Absorption 

by Muscle 433 

IV. On the Nature of Hemolysis 438 

V. On Growth and Some Growth Phenomena 446 

VI. On the Contraction of Catgut and the Nature of Muscle Contraction 451 

1. Observations on the Contraction of Catgut 452 

2. Interpretation of Experimental Findings . 459 

3. On the Analogy between the Described Contractions of Catgut 

and the Contraction of Striated Muscle 461 

4. Historical and Critical Remarks 463 



PART SIX 
NEPHRITIS 

I. The Thesis 473 

II. An Abnormal Production or Accumulation of Acid in the Kidney 

Occurs in Every Case of Nephritis 475 

III. Any Means which Leads to an Increased Production or Accumula- 
tion of Acid in the Kidney is a Means of Producing Nephritis 488 



xiv TABLE OF CONTENTS 

PAGE 

IV. Nephritis Due to Other than Acid Causes 502 

V. The Albuminuria . . . 504 

1. Introductory Remarks 504 

2. Observations on the ''Solution " of Colloid (Protein) Gels 508 

3. On the Relation between Swelling and "Solution" in Protein 

Colloids 519 

4. Critical Remarks 530 

VI. The Morphological Changes in the Kidney 532 

1. Introduction 532 

2. Classification of the Nephritides. Correlation of the Morpho- 

logical Changes in the Kidneys with Some Clinical Manifes- 
tations 533 

3. The Changes in the Size and in the Color of the Kidney in 

Nephritis (Cloudy Swelling) 540 

4. The Bleeding into and from the Kidney in Nephritis (Hemor- 

rhage by Diapedesis) 555 

5. On the Origin and the Different Types of Tube Casts 560 

VII. Some Responses to Criticism 567 

1. On the Swelling of Gelatin in Polybasic Acids and their Salts. . 567 

2. On the Liquefaction or "Solution" of Gelatin in Polybasic 

Acids and their Salts 596 

3. On the Swelling of Fibrin in Polybasic Acids their Salts 602 

VIII. On the Alleged Consequences of Kidney Disease 614 

1 . On the Relation of Vascular Disease to Nephritis 615 

2. On the (Edema of Nephritis 626 

3. On the "Uremia" of Nephritis. 628 

4. Reinterpretation of the Relation of Nephritis to the Clinical 

Manifestations Associated Therewith 629 

5. Remarks on the Etiology of Vascular Disease 634 

IX. The Disturbances in Secretion in Nephritis 636 

1. General Considerations 636 

2. The Secretion of Water by the Nephritic Kidney 638 

3. The Secretion of Dissolved Substances by the Nephritic 

Kidney 640 

X. Some Experimental Foundations for the Treatment of Nephritis. 

Fallacy of Salt Restriction in Nephritis and (Edema 648 

1. Introduction 648 

2. Asphyxial Nephritis 649 

3. Nephritis Produced by Injecting Acid 655 

4. Nephritis Due to Temporary Closure of the Renal Vessels 659 • 

5. Interpretation of Experimental Findings 663 

6. Inhibit ive Effects of Alkaline Salts on the Albuminuria of Hard 

Work 665 

XI. On the Treatment of Nephritis 667 

1. Introductory Remarks '. 667 

2. Diet in Nephritis 669 

3. Water Consumption in Nephritis 674 



TABLE OF CONTENTS xv 

PAGE 

4. The Role of Salts in Nephritis. 676 

5. More Aggressive Methods of Alkali and Salt Administration. . . 678 

6. The Treatment of Severe Cases of Nephritis . . . 686 

7. Clinical Abstracts and Comment 696 

8. Dehydration Therapy in Other (Edemas 731 

9. On (Edema as an Alleged Consequence of Sodium Chlorid 

Retention 731 

10. On the Treatment of Anasarca and Ascities. Comment on 

the Sodium Chlorid Restriction Therapy 738 

XII. Diagnosis and Prognosis in Nephritis 746 

1. Judging the Nephritic. Prognosis 746 

2. Underlying Principles and Clinical Value of Kidney Efficiency 

Tests 757 

3. On Acidity Measurements of the Urine 765 

4. Limitations of Indicator Methods 775 

5. Ammonia Determinations, Acetone Compounds, "Acidosis," 

and Coma 778 

XIII. Prophylactic Measures Against Nephritis. Care of the Surgical 

and Medical Patient 783 



PART SEVEN 
GLA UCOMA 

I. On the Nature and Cause of Glaucoma 795 

II. On the Relief of Glaucoma 797 

1. Local Measures 797 

2. Systemic Measures 799 

III. Some Comments 802 

IV. On the Nature of Corneal Opacities 806 

V. Closing Remarks 810 



PART EIGHT 
APPENDIX 

I. The Relation of Mouth Infection to Systemic Disease 815 

1. Introduction 815 

2. Historical Remarks 817 

3. Infections of the Blood Stream and Systemic Disease. 818 

4. Modification of Micro-organisms through Environment 821 

5. Fundamental Systemic Pathology 823 

6. Points of Entrance for Systemic Infection 832 

7. Illustrative Case Reports , . . . . 834 

8. Remarks on Some Dental Procedures 836 



xvi TABLE OF CONTENTS 

PAGE 

9. Some Suggestions 840 

10. The Foul Breath and the Coated Tongue 845 

11. On Extraction 848 

12. Concluding Remarks 851 

II. Diagnosis, Prognosis and Treatment in Nephritis. (A Clinical 

Lecture) 852 

1. (Edema in the Absence of Circulation 852 

2. The " Nephritis" of Heart Disease 854 

3. The Nephritis of General Intoxication 863 

4. Spotty Parenchymatous Nephritis Due to Infection of the Kid- 

ney (Infectious Nephritis) 876 

5. Spotty Parenchymatous Nephritis Due to Vascular Disease 

(Chronic Interstitial Nephritis) 880 

A. Ambulatory Type : 880 

B. The Cardiac Type with Chronic Interstitial Nephritis. 888 

C. The Cerebral Type with Chronic Interstitial Nephritis. . . . 890 



PART ONE 
THE ARGUMENT 



(EDEMA AND NEPHRITIS 



PART ONE 

THE ARGUMENT 

In this first part is given in running form a resume of the 
entire volume. The busy reader may accept as much of the 
argument as here outlined upon the abbreviated evidence accom- 
panying it as he chooses. By turning to the page references 
given in the text the detailed observations will be found on 
which are based the more dogmatically stated conclusions con- 
tained in these first paragraphs. 

PART TWO 

So practical a question as the treatment of glaucoma, uremia 
or anuria is intimately associated with the problem of oedema. 
This problem of cedema, the question of how a cell, an organism 
or the body as a whole comes to hold an abnormally large amount 
of water is in its turn but a subheading of that still greater prob- 
lem, why living matter holds any water at all and why under nor- 
mal circumstances it holds so constant an amount. Various 
hypotheses have been proposed by animal and plant physiologists, 
by pathologists and clinicians to explain such normal and ab- 
normal water absorption, but all are inadequate to account for 
more than the smallest fraction of the phenomena observed. 

The absorption of water by living matter under physiological 
and pathological circumstances is determined by the colloids 
contained in it and their state. The major portion of the 
chemical substances which make up protoplasm exists there in 

3 



4 



(EDEMA AND NEPHRITIS 



colloid form. A discussion of the properties of colloids with 
particular reference to the matter of water absorption is there- 
fore in order. (See pages 41-44.) 

About the middle of the last century it was noted that chem- 
ical substances differ in the rate at which they diffuse through 
solvents. The group which diffuse but slowly and which are 
for the most part amorphous, of high molecular weight, without 
osmotic pressure, and pseudo-soluble, are known as colloids, 
while those which diffuse rapidly, are of low molecular weight, 
have osmotic pressure, and form true solutions, are known as 
crystalloids. Among the former are found glue, gelatin, albumin 
and starch; among the latter, cane sugar, common salt and urea. 
While we are seemingly classifying substances we should really 
speak of the colloid and crystalloid states, for later observations 
have shown that it is not its chemical character which identifies 
the colloid, but rather the physical state of the substance, prac- 
tically all substances being capable of existing in either of these 
two forms. (See pages 44-49.) 

The colloids themselves do not all show the same properties. 
On the one hand there are those which enter into close association 
with their solvent (lyophilic or hydrophilic colloids) ; on the other, 
those which do not (lyophobic or hydrophobic colloids) . Gelatin, 
dextrin, starch, glue, vegetable fibers, albumin and gums are 
examples of the former class; the colloid metals, metallic hy- 
droxids and sulphids are examples of the latter. (See pages 49- 
61.) 

The former of these two groups is of greatest biological im- 
portance, for the bulk of protoplasm is made of it. An attempt 
is therefore made to define the difference between the two groups 
more closely. Beginning with the now generally accepted belief 
that a colloid system results whenever one material is divided into a 
second with the degree of subdivision coarser than molecular and 
not yet so coarse as to come into the physical realm of the mechani- 
cal mixtures, it is pointed out that a hydrophobic or lyophobic 
colloid results whenever the subdivided material is not a solvent 
for the dispersion medium; a hydrophilic or lyophilic colloid when 
the subdivided material is such a solvent. Illustrations are intro- 
duced of the different types of systems that may be thus produced. 
Beginning at the top is a system consisting of a true solution of 
a in b while at the bottom is another true solution of b in a. Be- 



THE ARGUMENT 



5 



tween these extremes exist two zones of mixed systems, one under 
the topmost consisting of a subdivision of solvated a particles in a 
solution of a in b, and below this a system of reverse type, namely, 
one of a subdivision of a solution of a in b in hydrated a as an envel- 
oping or external phase. On the basis of the existence of these 
different systems are explained the meanings of such terms as 
solubility, solvation capacity, swelling, sol and gel, gelation 
capacity, syneresis and hysteresis. 

To discover some of the properties of the lyophilic colloids, 
particularly their relation to the absorption of solvent, the biologic- 
ally important colloids, fibrin, gelatin, gluten, aleuronat and 
blood serum are studied. (See pages 61-151.) 

Fibrin absorbs more water (swells more) in any acid solution 
than it does in pure water. Within certain limits the amount 
of water thus absorbed increases with the concentration of the 
acid, but when a certain concentration is exceeded the fibrin 
swells less than in lower concentrations. The same is true of 
alkalies. The addition of any salt, even a neutral salt, to the 
solution of any acid or alkali reduces the amount that the fibrin 
swells and this the more the higher the concentration of the 
salt. When equivalent concentrations of different salts are 
compared some are found more active in this regard than others. 
Thus, the chlorid, bromid and iodid are less capable of dehy- 
drating fibrin than the acetate, while yet more powerful are the 
sulphate, phosphate and citrate. When the effects of basic 
radicals are compared potassium, sodium and ammonium are 
found less active than magnesium, calcium or strontium, while 
copper and iron are most effective of all. Non-electrolytes 
are comparatively ineffective in reducing the swelling in the 
presence of an acid or alkali. They are not, however, entirely 
without effect. Among the non-electrolytes the sugars deserve 
special mention because these produce a considerable dehydrating 
effect. When dextrose, levulose and saccharose are compared 
the last named is found particularly powerful. The taking 
up and giving off of water by fibrin represents in large measure 
a reversible process. In addition to the acids and alkalies there 
exist a number of other substances which are capable of increasing 
its hydration capacity. Urea and pyridin and possibly some 
of the amins are to be mentioned in this class. The hydrations 
produced by these substances are of a different type from those 



6 



CEDE MA AND NEPHRITIS 



produced by acids and alkalies, for they are not readily reducible 
through salts, while they are through various non-electrolytes 
(sugars), a behavior the opposite of that observed in acid or 
alkali hydration. (See pages 61-75.) 

What has been said of fibrin is not characteristic of it alone, 
but is true of all proteins, as illustrated by the identical behavior 
of gelatin, gluten and aleuronat. (See pages 75-145.) 

What has been said of the solid colloids holds also for the 
liquid colloids such as blood serum, fluid gelatin or egg white. 
The hydration and dehydration in such liquid colloids can be 
followed by noting the changes in their viscosity, hydration 
being betrayed by an increase in viscosity, dehydration by a 
decrease. (See pages 145-151.) 

The behavior of the more solid colloids corresponds to the 
behavior of the more solid constituents of our body, as the tissues ; 
that of the liquid with the fluids permeating these solid structures, 
namely, the blood, the lymph, the cerebro-spinal fluid, etc. 

It can be shown that every tissue takes up water or gives it 
off under conditions identical with those which cause protein 
colloids to do this. Thus, muscle, eyes or nervous tissues swell 
more in acid or alkali than in water, and this the more, within 
certain limits, the higher the concentration. Beyond a certain 
optimal concentration the tissues begin to lose water. The 
addition of any salt to the acid or alkali produces a dehydrating 
effect, and this is the greater the higher the concentration of the 
salt. At the same concentration different salts are unequally 
effective, and here again their order parallels that observed on 
simple proteins. The non-elect rolytes as compared with the 
elect rolytes are less effective. The processes of hydration and 
dehydration in all these tissues are largely reversible. Urea is 
observed in all these tissues to lead to an increased hydration. 
(See pages 151-192.) 

The acceptance of the view that the colloids of the tissues 
and their state are primarily responsible for the amount of water 
held by them constitutes a tacit criticism of every theory of water 
absorption thus far advanced. These theories may be called 
for short, the osmotic theory conjointly with which we may 
consider that modification of it known as the lipoid membrane 
theory, and the pressure theory. The pressure theory is criticised 
later. (See pages 193-195.) 



THE ARGUMENT 7 

The osmotic theory assumes that cells are surrounded by semi- 
permeable membranes through which water but no dissolved 
substances can pass. The movement of water is occasioned 
by differences in the concentration of dissolved substances within 
and without the cell, the water being carried in the direction 
of the higher concentration whether existing within or without the 
cell. In thus accounting for the migration of water into and out 
of cells it becomes impossible to get dissolved substances through. 
Such a conception of the living cell is an impossible one because 
the cell must be and is able to absorb all manner of foodstuffs 
and get rid of the products of its metabolism. To meet this 
situation the original osmotic theory has been modified by saying 
that the membrane is permeable to some or all substances at some 
or all times. But when this postulate is granted concentration 
differences between the inside and the outside of the cell can 
no longer come to pass, for the dissolved substances will simply 
move from regions of higher to regions of lower concentration. 
The forces active for the movement of water therefore disappear. 
Adherents of the osmotic theory can move either water or dis- 
solved substances, but they cannot move both, and yet in living 
cells this must be possible. (See pages 195-201.) 
1 The lipoid membrane theory suffers from much the same 
defects as the original osmotic one. In assuming the outer layer 
of cells to be fatlike in character, it may become possible to 
explain more easily the entrance of fat-soluble substances, but 
since fat is no solvent for water, for salts and for many of the 
normal products of cell metabolism, this conception is also bio- 
logically impossible, for all these can and must be able to pass 
into and out of cells. (See pages 201-203.) 

The mosaic theory, which holds part of the cell membrane 
to be 11 protoplasmic " in character, another part lipoid, suffers 
from the combined defects of the osmotic and lipoid theory. (See 
page 203.) » 

In the colloid-chemical theory there is no need for membranes 
about the cells. The absorption of water is governed by the 
laws which govern the hydration and dehydration of lyophilic 
colloids. The differences between the concentration of dissolved 
substances found inside and outside of the cell are accounted 
for through differences in relative solubility, differences in ad- 
sorption and differences in chemical constitution. The cell 



8 



OEDEMA AND NEPHRITIS 



conceived of as a colloid matrix can not only absorb and secrete 
water, but it can also absorb and secrete any dissolved substance 
at the same time, and the two processes may run in the same 
direction or in opposite directions as physiological and biological 
observation demands. (See pages 204-206.) 

The conception that cells are surrounded by osmotic or lipoid 
membranes has been used to explain not only the absorption 
of water, but also the biological characteristics of the absorption 
of dissolved substances. In essence this problem asks why dif- 
ferent parts of the same cell or different cells bathed by the same 
blood and lymph do not all hold the same amount of dissolved 
substance. The membrane theory attempts to explain such 
concentration differences by saying that the membranes are 
partially permeable or impermeable to these dissolved sub- 
stances. In discarding the osmotic conception of water absorp- 
tion we discarded also this mechanism for the maintenance of 
concentration differences. What have we to put in its place? 
(See pages 206-207.) 

We are familiar in physical chemistry with a number of 
illustrations of inequalities in the distribution of dissolved sub- 
stances between different phases even though no membranes exist 
between them. Thus, when a substance is more soluble in one 
solvent than in another, it will collect in greater concentration 
in that in which it is the more soluble; or the adsorption pro- 
perties of the colloids may be different as in different cells; or 
the presence of certain chemical compounds in one phase 
permits it to combine chemically and so hold a greater amount 
of a given dissolved substance than another phase in which 
such are not present or present in less amount. Finally, all 
three may be active at one and the same time. (See pages 
208-213.) 

On this basis our conception of the cell becomes that of a 
mass of protein intimately mixed with more or less fat and fat- 
like material, the whole immersed in a liquid from which the 
protein-fat mixture soaks up a certain amount of water and of 
various substances dissolved in the water, the whole being gov- 
erned by the laws of equilibrium. (See page 213.) 



THE ARGUMENT 



PART THREE 

The problem of oedema is also a problem in colloid-chemis- 
try — that of the ways and means by which the normal hydra- 
tion capacity of the body colloids is heightened. The school of 
pathologists quite generally upholds the teaching that oedema 
is produced by changes in the pressure of the circulating fluids 
of the body (increased blood and lymph pressure) together with 
an increase in the permeability of the vessel walls. This pressure 
theory is completely unsatisfactory, for not only may we have 
extreme degrees of oedema without changes in blood or lymph 
pressure, but measures which increase blood pressure and should 
therefore increase oedema are known to produce just the oppo- 
site effect. In place of the pressure idea, changes in the tissues 
and cells have therefore been made to play a role in the develop- 
ment of oedema, but the attempt to define clearly the real nature 
of these was not made until quite recently when it was taught 
that increases in the osmotic pressure of the cell contents might 
lead to an increased absorption of water and thus to oedema. 
(See pages 217-220.) 

The cause of cedema resides in the tissues, which become 
cedematous not because water is forced into them, but because 
they suffer changes which make them suck up water. This is 
proved by the fact that the severest grades of cedema may be 
produced in the entire absence of any circulation, and conse- 
quently in the entire absence of any blood pressure. (See pages 
220-232.) 

A state of cedema is induced whenever, in the presence of an 
adequate supply of water, the capacity of the tissue colloids for 
holding it is increased above that which we are pleased to call 
normal. Any agency capable, under the conditions . existing 
in the body, of thus increasing the hydration capacity of the tissue 
colloids constitutes a cause of cedema. The accumulation of 
acids within the tissues, brought about either through their 
abnormal production or through the inadequate removal of such 
as some consider normally produced in the tissues, is chiefly 
responsible for this increase in the hydration capacity of the 
colloids, though the possibility of explaining at least some of it 
through the production or accumulation of substances (of the 
type of urea, pyridin, certain amins, etc.) which hydrate col- 



10 



(EDEMA AND NEPHRITIS 



loids as do acids, or through the conversion of colloids having 
but little capacity for water into such as have a greater capacity 
must also be borne in mind. (See pages 232-233.) 

As it has already been proved that the amount of water 
absorbed by a tissue is dependent upon its content of lyophilic 
colloids it must next be shown that conditions capable of in- 
creasing their normal hydration capacity are produced in 
all states of oedema. Of those that might be discussed, an ab- 
normal production and accumulation of acids is considered the 
most potent, wherefore it receives detailed consideration. (See 
page 233.) 

The proof that such occurs in all states of oedema consists 
of the following:. An abnormal production or accumulation of 
acids or conditions predisposing thereto exist in all states in which 
we encounter cedema. Circulatory disturbances, whether gen- 
eralized or local, conditions which decrease the oxygen-carrying 
powers of the blood, as the anemias, various states of inanition, 
the fevers, the chemical changes following death, as well as 
poisons of various kinds which are followed by oedema, all repre- 
sent methods by which the chemistry of the tissues is so altered 
as to lead to an abnormal production or accumulation of acid 
in them. (See pages 233-243.) 

Conversely, any means by which an abnormal production 
and accumulation of acid may be brought about in a tissue is 
followed by an oedema. Thus, the acid production occurring 
in tissues after death or in poisoning by arsenic, morphin, uran- 
ium, chloroform, ether, cocain, etc., is always followed by a reten- 
tion of water in the body and an oedema. (See pages 243-249.) 

Finally, those conditions which are capable of decreasing 
the hydration of protein colloids decrease oedema, while those 
which are ineffective in this regard do not do so. Thus, the 
cedemas developed by amputated frogs' legs laid in water are 
reduced by all salts, and this the more the higher their concen- 
tration. At the same concentration different salts are unequally 
effective in this regard, and this in the order in which they de- 
hydrate simple proteins swelling in the presence of acid. To 
meet the criticism that such reduction of oedema is possible in 
" dead " frogs' legs but not in " living " animals, a parallel series 
of experiments is introduced on " living " frogs made cedematous 
by injections of uranium. Sodium chlorid is no exception to the 



THE ARGUMENT 



11 



rule; it reduces eedema as does any other salt. (See pages 
249-262.) 

The possible role of other agencies besides an increased acid 
content in the development of oedema is discussed, and the 
importance of such known hydrating substances of protein as 
the alkalies, urea, pyridin and the amins is emphasized. (See 
pages 262-268.) 

A number of the specific problems presented by oedema as it 
affects special organs is next considered. Thus, another explana- 
tion must be found for the generally accepted belief that the 
oedema observed in a passively congested kidney, produced, 
for example, by ligation of the renal vein, is due to an increased 
capillary pressure and a forcing of fluid into the kidney tissues. 
Ligation of the renal artery with its consequent decrease in blood 
pressure is followed by exactly the same kind of change. (See 
pages 268-271.) 

Such a result, which cannot be interpreted by any of the older 
work, is readily understood on the colloid-chemical basis. Whether 
we deprive an organ of its oxygen supply by preventing the normal 
efflux of blood from it, or by preventing the normal influx, the 
resulting accumulation and production of acid is, of course, the 
same, and so it was to be anticipated that the organ would swell 
equally in both cases. (See pages 271-276.) 

This idea can be further tested on the liver, which besides 
ha zing a (venous) blood supply through the portal vein, receives 
a second (arterial) blood supply through the hepatic artery, 
the two blood streams leaving the liver through the hepatic , 
vein. Ligation of the portal vein does not lead to an oedema 
of the liver, but an extreme grade of it is produced when the 
hepatic artery is tied, even though there results herefrom a fall 
in blood pressure. Passive congestion oedema of the liver sec- 
ondary to heart disease is really produced through interference 
with the normal oxygen supply to the parenchyma of the liver 
through the hepatic artery due either to a deficient blood flow 
because of a defectively acting heart, or because the overfilled 
veins dam back the arterial blood so that it cannot get into the 
liver. (See pages 272-276.) 

The problem of pulmonary oedema is essentially the same 
as that of the passive congestion oedema of the liver, for the 
lung also has two blood supplies, the pulmonary circuit and a 



12 



(EDEMA ANb NEPHRITIS 



i 



supply of arterial blood through the bronchial arteries. While 
interferences with the pulmonary circuit scarcely lead to an 
oedema of the lungs, such is promptly produced by interference with 
the systemic circulation. The most potent method of producing 
a pulmonary oedema consists in interfering with the oxygen supply 
through the bronchial arteries. (See pages 276-282.) 

It remains to account for the accumulations of fluid, so fre- 
quently encountered in states of oedema, in the serous cavities 
and " tissue spaces/' These accumulations represent dilute 
solutions of protein. The squeezing off of such dilute colloid 
mixtures (the " transudates ") by more concentrated and solid 
ones (the cedematous tissues) is analogous to the syneresis ex- 
hibited by colloids. When heavily hydrated solid colloids such 
as silicic acid or gelatin are permitted to stand, a thin colloid 
solution separates from them after a time. Such separation is not 
noted in slightly hydrated colloids, but is marked in heavily 
hydrated ones, and increases with time. In the same way the 
severer and more chronic types of oedema are the most likely to 
be accompanied by accumulations of fluid in the serous cavities 
and " spaces." (See pages 283-285.) 

Some concluding sentences indicate how the experimental 
findings on oedema of older observers are to be interpreted in 
the terms of the colloid-chemical theory. (See pages 285-289.) 

PART FOUR 

The problem of absorption and secretion in the higher animals 
seems at first sight very different from this same problem in so 
simple a structure as the individual cell or tissue. The ameba, 
for instance, takes up or gives off water according to changes in 
its surroundings, whereas in a complex organism we find whole 
organs seemingly set apart for absorption or secretion alone. 
But we need to appreciate that the mucosal cell, for example, 
is an absorbing cell only so long as we look at it from the side of 
the lumen of the gut. From the blood vessel side it is a secreting 
cell, for what it absorbs from the gut it gives up to the blood. 
What characterizes absorption and secretion in the higher animals 
is that under normal circumstances and from the point of view 
of the organism as a whole, absorption and secretion occur pre- 
dominantly in one direction. The reason for this resides in the 



THE ARGUMENT 



13 



fact that unlike the ameba which is surrounded on all sides by 
the same medium, the cells of an absorbing or secreting organ 
(in a mammal, for example) are through different portions of 
their cell protoplasm in contact with entirely different media. 
The effort to get into equilibrium with these produce all the 
phenomena of absorption and secretion characteristic of the 
higher animals. (See pages 293-296.) 

Every absorbing system consists of three phases: 

1. The material to be absorbed — essentially an aqueous solu- 
tion of dissolved substances. 

2. An absorbing membrane — physico-chemically, a solid col- 
loid behaving not unlike a leaf of gelatin. 

3. The blood and lymph — a liquid colloid acting, as a whole, 
like a (liquid) solution of gelatin. With it are admixed various 
solid colloids known as blood cells. (See pages 296-299.) 

In discussing absorption we must at all times distinguish 
between the absorption of water and the absorption of the dis- 
solved substances in the water. Absorption from the peritoneal 
cavity is first taken up. When water is introduced into the 
peritoneal cavity it is quickly absorbed. This is. because the 
colloids of the peritoneum in consequence of their constant car- 
bonic acid production are not saturated with water. When the 
arterial blood enters the peritoneum the carbonic acid produced 
in the cells is given off to it. This increases the hydration capacity 
of the blood colloids, which therefore take water out of the peri- 
toneum. As long as the circulation is maintained and the cells 
continue to produce carbonic acid, absorption of water must 
therefore occur. (See pages 299-306.) 

All salt solutions are absorbed more slowly than pure water. 
This is because the salts diffuse into the eolloid absorbing mem- 
brane and tend to dehydrate it, thus starting a counterstream 
of water secretion to meet the normal stream of water absorption. 
The end result so far as the absorption of water is concerned 
will represent the algebraic sum of the two. The higher the 
concentration of the salt solution the greater the counterstream 
and consequently the slower the absorption of water from the 
peritoneal cavity. (See pages 306-307.) 

At the same concentration the different salts in solution delay 
in different degrees the absorption of water, and this in the order 
in which they tend to dehydrate protein colloids. The non- 



14 



(EDEMA AND NEPHRITIS 



electrolytes as compared with the electrolytes are rather in- 
effective. Only glycerin and the sugars delay definitely the 
absorption of water by the peritoneum. Both acids and alkalies 
delay it also. When water is offered the peritoneum in the form 
of a colloid solution, in a form, therefore, in which it is bound to 
the colloid, it cannot be absorbed. This is why blood, lymph 
and ascitic accumulations remain for long periods in the peri- 
toneum, while pure water, dilute salt solutions, etc., are readily 
absorbed. (See pages 307-311.) 

The available facts on the absorption of water by the intestine 
are explained in identical fashion. Water is absorbed best, 
and colloid solutions, in which all the water is bound to the colloid, 
not at all. All salts delay the absorption of water, and this the 
more the higher the concentration of the salt. Different salts at 
the same concentration are unequally effective in this regard. 
A saline cathartic is merely a salt which is very powerful in its 
dehydrating effect without possessing marked poisonous action. 
(See pages 311-315.) 

Critical remarks on previous theories of absorption are entered 
into and the laws governing the absorption of dissolved sub- 
stances discussed. (See pages 315-325.) 

Secretion represents the mirror image of absorption. In 
this problem, as in absorption, we need again to distinguish 
between the secretion of water and the secretion of any dissolved 
substance in the water. As the kidney represents from both a 
qualitative and a quantitative point of view the great secreting 
organ of our bodies, it receives chief consideration, though what 
is said of it may with little modification be applied to any of the 
other secretory organs, as the skin, salivary glands or stomach. 
(See pages 325-326.) 

A secreting system in a complex organism is made up of three 
phases : 

1. A secretion which for the most part represents a watery 
solution of various crystalloids. 

2. A secreting membrane which may be likened to a solid 
colloid like a leaf of gelatin. 

3. A source of some kind, the liquid colloid known as blood 
or lymph. (See pages 326-327.) 

A model is described which illustrates some phases of urinary 
secretion. It consists of a layer of fibrin through which solutions 



THE ARGUMENT 



15 



of various kinds may pass at constant pressure. Water or a 
" physiological " salt solution passes through at a certain rate. 
An acid solution makes the fibrin swell and lowers the amount 
of " secretion " to the point of stoppage. When to this acid 
is added any salt the fibrin shrinks and the secretion recommences, 
the saline diuretics acting more powerfully in this regard than 
other salts. When acid passes through, the fibrin goes into 
solution so that an albumin ring is obtainable; this also disap- 
pears on the addition of salts. (See pages 327-330.) 

The kidney can secrete water only as it is furnished this organ 
in " free " form, In absolute starvation no free water comes to 
the kidney and so secretion ceases. On the other hand, the 
giving of water by mouth, intraperitoneally, subcutaneously or 
intravenously, increases the secretion according to the amount 
given (loss through lungs, skin, etc., ignored). (See pages 330- 
331.) 

When sodium chlorid solutions of different concentrations are 
injected intravenously, the amount of urine given off increases 
with the concentration of the salt, a point being finally reached 
where the water output is greater than the amount injected. Such 
a result is usually interpreted by saying that the salt "stimu- 
lates" the kidney and thus, as it were, pulls water out of the 
blood. What really happens is that the salt content of all 
the tissues of the body is increased, in consequence of which 
they give up water, and this " free " water is then added to the 
amount that is being injected. The " diuretic " action, there- 
fore, really depends primarily upon an effect on the body as a 
whole and only incidentally on the kidney. (See pages 331-336.) 

The conclusion that only free water can be given off by the 
kidney can be tested by injecting instead of a salt solution a 
colloid solution in which all the water is bound to the colloid. 
Injection of no amount of blood or blood serum increases the 
output of water from the kidney. (See pages 336-339.) 

The saline diuretics produce their diuretic action as do the 
stronger sodium chlorid solutions by their effect upon the body 
as a whole. They act primarily not upon the kidney, but after 
injection intravenously diffuse into the tissues, and, dehydrating 
them, aid in bringing free water to the kidney. The diuretic 
action of any salt is predictable by adding together the dehy- 
drating effect of its constituent radicals upon a simple protein. 
(See pages 339-349.) 



16 



(EDEMA AND NEPHRITIS 



Those non-electrolytes which are capable of producing some 
dehydration of simple protein colloids are also able to dehydrate 
the body colloids and so to produce diuresis. This diuretic action 
is again to be attributed, in the main, not to an effect upon 
the kidney, but to an effect upon the body as a whole. Just 
as dextrose and levulose produce equal degrees of dehydration 
in simple protein colloids, they have when injected intravenously 
an equal diuretic action. Saccharose, on the other hand, which 
acts more powerfully on pure proteins, also acts more powerfully 
as a diuretic. As the sugars are relatively more effective in 
producing protein dehydration in high concentrations than in 
lower ones (the opposite of what is true for salts), they also 
produce a relatively greater diuresis in the higher concentrations 
than in the lower. The dehydrating effect of sugar helps to ex- 
plain not only the dryness of the diabetic's tissues, but his thirst 
and his increased urinary output. (See pages 349-357.) " 

In order to secrete properly the kidney must be well supplied 
with oxygen. This explains why every scheme which interferes 
with the normal oxygen supply to the kidney or with the proper 
utilization of oxygen in the kidney is followed by a diminution in 
the urinary output. Agencies which are capable of aiding in the 
restoration of a normal oxygen supply to a kidney suffering from 
its lack constitute a second method of producing diuresis. This 
is why caffein and its derivatives, digitalis, etc., which favor respi- 
ration and the circulation of arterial blood through the kidney, act 
as diuretics, while, on the other hand, chloroform, ether and alcohol 
which in large doses lead, in toto, to a state of lack of oxygen in the 
tissues, all decrease the urinary output. Drugs like caffein, 
digitalis, etc., I shall call for short diuretics of the second order. 
(See pages 357-362.) 

The soundness of these ideas on urinary secretion is tested 
by applying them to the interpretation of the experimental results 
of other authors. (See pages 362-365.) 

It is pointed out that the transition from the physiological 
to the pathological in kidney function is not abrupt, but that we 
pass gradually from such a state as is considered normal to that 
in which we recognize the pathological extreme of a parenchyma- 
tous nephritis. (See pages 365-367.) 

The secretion of dissolved substances by the kidney (or any 
other organ) is a problem that must be considered independently 



THE ARGUMENT 



17 



of the secretion of water. A secretion of water is necessary 
before we can get the secretion of any dissolved substance. Urine 
is secreted primarily as water, and only secondarily as it washes 
down the tubules do substances come to be dissolved in it, giving 
it the qualities of urine. The feature which it has been difficult 
to explain in secretion is the quantitative differences between 
the concentration of any dissolved substance in the blood and 
the concentration of this same substance in the urine. Upon the 
existence of such differences has been based a faith in a " vital " 
element in secretion. Actually, such a conception is premature 
if not absurd. The distribution of a dissolved substance be- 
tween any three such phases as blood, kidney substance and water 
(the original urine) is a matter of equilibrium, and this is by no 
means always attained when the concentration is the same in 
all. The equilibrium point may be shifted in either direction, 
depending upon the solution properties, the adsorption char- 
acteristics and the chemical nature of the three phases. (See 
pages 367-370.) 

A second urinary model is described to show how many of the 
"mysterious" properties of such a secretory system as that repre- 
sented by the kidney may be understood in the simple terms of 
colloid chemistry. The kidney parenchyma is compared with a 
hydrolyzable salt, like ferric chlorid or sodium-gelatin-phosphate, 
subject to dialysis against water. The ferric chlorid or protein 
salt undergo hydrolysis with the one fraction (iron or protein) 
coming down in colloid form while the other (the acid) being 
crystalloid and readily diffusible passes into the surrounding water 
to yield a "secretion", more acid than the medium from which it 
is derived. This is normal urinary secretion in which circum- 
stances a solution of crystalloids, acid in reaction, is being obtained 
from a less acid colloid matrix. If acid is introduced into the 
colloid matrix it makes this "go into solution" wherefore iron or 
protein appears in the surrounding wash water. This is the ana- 
log of the "solution" of the kidney proteins in the urine when 
the kidney is subjected to the action of an accumulation of acids or 
like-acting substances. (See pages 371-380.) 

The question of the mechanism by which water is secreted from 
such a secreting parenchyma as the kidney is raised in a third 
model of secretion. The evidence is reviewed which supports the 
conclusion that such secretion represents a mere nitration process 



18 



(EDEMA AND NEPHRITIS 



and since the secreting parenchyma of such an organ as the kidney 
is a hydrated colloid with properties closely akin to a solid hydrated 
soap, the filtration properties of such a soap are studied. Cups of 
solid sodium stearate are chosen. Water passes through such a 
cup only when free; hydrated liquid colloids comparable to blood 
remaining in the cup indefinitely. Salt solutions filter through 
more rapidly than plain water according to (a) their concentration 
and (6) then kind. The higher the concentration the more rapid 
the filtration. On the other hand, salts of ammonium or potassium 
produce less filtration than salts of sodium and these less than 
those of magnesium or calcium (just as in the case of urinary 
secretion in an animal). When the effects of equally concen- 
trated salts with the same basic but different acid radicals are 
compared, no such diuretic differences appear as occur in animals. 
The theory of the action of these effects is discussed, it being 
pointed out that because of the existent differences in chemical 
composition of fatty acids and of the polymerized amino-acids 
known as protein, it is possible in the former to produce only one 
series of salts (as different bases are introduced into the fatty 
acids) while in the case of the proteins a similar series may be 
produced but, because of the existence in the latter of NH2 groups, 
a second series may also be produced through the finking of acid 
with these groups. Colloid-chemical and physiological behavior 
are then an expression of the solvation and solubility properties 
of the different compounds thus formed. (See pages 380-397.) 

The formation of lymph is in many respects analogous to the 
secretion of urine and is governed by similar laws. Anything 
that makes the cells or tissues of an organ give up water increases 
lymph flow, a lymphagogue being any substance which will aid 
in dehydrating the tissues of the body. (See pages 397-398.) 

Some remarks on the vasomotor mechanism follow. Changes 
in the amount of blood going to a gland are controlled by this. 
As we would expect, vasodilatation with its better supply of 
oxygen and free water makes for secretion, while vasoconstriction 
does the reverse. Vasodilatation with an adequate arterial blood 
flow may take place and yet there be no secretion from a gland, 
but only when poisons have been introduced which keep the gland 
from utilizing the oxygen. During their so-called periods of 
rest the gland cells swell and develop granules, while during 
activity they shrink and the granules disappear. The compli- 



THE ARGUMENT 



19 



cated interpretation given these facts is replaced by the simple 
statement that in the absence of a circulation the gland cells 
develop an oedema which disappears when the blood vessels 
dilate and more oxygen becomes available. The granules repre- 
sent precipitates of a second colloid as the acid content runs 
up, which disappear when with a better oxygen supply the acid 
is removed. A so-called resting gland represents the parallel 
of what in pathology we call cloudy swelling. The existence of 
secretory nerves is questioned. They are vasomotor nerves. 
The "distribution of secretory nerves and vasomotor nerves is 
identical. Secretion does not occur without coincident vaso- 
dilatation. Vasodilatation may occur without secretion, as when 
defectively oxygenated blood is furnished, but the reverse, never. 
A large arterial blood supply is furnished to some glands con- 
stantly, to others temporarily through vasodilatation governed 
by nerves. (See pages 398^00.) 

Whatever favors secretion interferes with absorption, and 
vice versa. (See pages 400-403.) 

Looking at the problem of secretion from another viewpoint it 
is now asked why all the blood does not pass out of the body as 
urine or some other secretion. Why does the blood remain in the 
blood vessels? The blood remains in them because all its water is 
bound to colloids. It is for this reason that the intravenous 
injection of no amount of blood or of any other colloid solution in 
which all the water is combined with colloid is followed by an in- 
creased urinary output. On the other hand, a salt solution at once 
leaves the body because its water is " free." The lymph remains 
in the lymph vessels for the same reason, (See pages 403-415.) 

These facts are of importance in establishing the principles 
that must guide us in any attempt to increase the blood pressure 
in patients suffering from an abnormally low one. The salt 
solutions injected into the blood vessels by way of increasing 
the pressure produce their good effects but temporarily because 
they consist of free water which leaves the body in the secretions 
or is sucked out of the blood vessels into the tissues. Only 
transfusion mixtures in which all the water is held in colloid 
combination can remain in the blood vessels. It is for this reason 
that transfusion with blood, blood serum, hydrocele fluid, ascitic 
fluid or a properly prepared gelatin solution yields good and 
lasting results. (See pages 415-422.) 



20 



(EDEMA AND NEPHRITIS 



How these principles have been utilized by various workers 
dealing with the practical problem of shock during the Great War 
is outlined. (See pages 423-426.) 

PART FIVE 

The normal, abnormally low and abnormally high water 
content of cells discussed by the biologists under the terms turgor, 
plasmolysis and plasmoptysis are next considered, and it is 
indicated how these phenomena as observed in spermatozoa, 
epithelial cells, white blood corpuscles, muscle and other cells 
and tissues when subjected to the action of acids, alkalies, salts 
and various non-electrolytes, are more easily explained through 
colloid-chemistry than through the older, more popular " osmotic " 
notions of water absorption. (See pages 429-438.) 

The problem of hemolysis receives special consideration. It 
is shown that changes in the size of the red blood corpuscles 
and the escape of hemoglobin from them are frequently asso- 
ciated, but not identical, processes. The changes in size follow 
the laws of water absorption by simple colloids, the loss of color 
entirely different ones. The hemoglobin and the stroma of the 
corpuscle are united as an adsorption compound similar in nature 
to the combination existing between certain colloids and dyes. 
The parallelism between the laws governing the absorption of 
water and the loss of color by carmine-stained fibrin and the ab- 
sorption of water and loss of color by red corpuscles is described 
in detail. (See pages 438-445.) 

The source of the energy for growth, which is defined as in- 
crease in volume, is found in the swelling of the colloids produced 
in the process of growth. The mechanism by which curvatures 
are produced in consequence of the directive action of various 
external stimuli (tropisms due to light, heat, chemicals, elec- 
tricity, water) is found in the unequal swelling of hydrophilic 
colloids, and it is indicated how many of these phenomena can 
be mimicked in the laboratory by the use of cylinders, strips 
and leaves of gelatin irregularly painted with acids, alkalies 
and other substances. (See pages 446-451.) 

Catgut strings when subjected to the action of acids shorten. 
This shortening is due to an absorption of water. They lose 
their water and lengthen again when the acid is washed out or 



THE ARGUMENT 



21 



neutralized. Various salts affect this contraction and relaxation, 
entirely similarly to the way in which they affect the absorption 
and giving off of water by various protein colloids. When such 
contractions are registered upon a drum, a series of curves is 
obtained identical with those produced by the contraction and 
relaxation of muscle. By varying the conditions surrounding 
the catgut the. phenomena of rigor, fatigue, staircase, residual 
contraction, increased tone and tetanus can be mimicked. The 
analogy between the contraction and relaxation of catgut and 
the contraction and relaxation of muscle under similar circum- 
stances leads to the conception that the muscle contraction 
represents a problem in colloid-chemistry, the contraction repre- 
senting a swelling and shortening of the muscle fibrils under the 
influence of a temporary acid production; the relaxation, the 
neutralization of this acid with loss of water. The contributions 
of various authors toward the establishment of such a colloid- 
chemical theory are reviewed. (See pages 451-470.) 

PART SIX 

The term nephritis is used to cover that symptom complex 
which clinically is characterized by the appearance of casts 
and albumin in the urine, by certain morphological changes in 
the kidney, by changes in the amount of water given off, by 
changes in the amount of dissolved substances secreted in the 
urine and by the associated oedema, increased blood pressure 
and cardiac hypertrophy. The changes that characterize nephri- 
tis are colloid-chemical in nature and due to a common cause — 
the abnormal production or accumulation of acid and of sub- 
stances which in their action upon colloids behave like acid in 
the cells of the kidney. To the action of these upon the colloid 
structures that make up the kidney are due the albuminuria, 
the specific morphological changes noted in the kidneys, the 
associated production of casts, the quantitative variations in 
the amount of urine secreted, the quantitative variations in the 
amounts of dissolved substances secreted, as well as the other 
signs of nephritis which appear in direct connection with the 
kidney. The alleged consequences of kidney disease such as 
cedema, high blood pressure, uremia, etc., are not consequences, 
but accompanying signs and symptoms which demand separate 



22 



(EDEMA AND NEPHRITIS 



discussion and analysis. Proofs of the correctness of these 
contentions follow two lines: 

1. A consideration of the chemical factors which bring about 
the colloid changes. 

2. A consideration of the colloid changes themselves. (See 
pages 473-475.) 

As under the first heading, an abnormal production and 
accumulation of acid is considered of chief importance, it re- 
ceives main emphasis. The proof that an abnormal production 
or accumulation of acid occurs in the kidney in every case of 
nephritis comes from three directions: 

1. The acidity of the urine determined either by titration 
or by measurement of its hydrogen ion content is constantly high. 

2. The blood shows a so-called decreased alkalinity. 

3. Dyes of various kinds which show a characteristic color 
only when the acid content of a tissue is sufficiently high and 
which show no color when injected into normal tissues, stain 
the kidneys when the signs and symptoms of a nephritis are 
present. (See pages 475-488.) 

On the other hand, it can be shown that any method which 
leads to an increased production or accumulation of acid in the 
kidney is a means of producing nephritis. Direct introduction 
of sufficient acid into the organism is followed by the appear- 
ance of casts and albumin in the urine and a diminished output 
of water. When the acid is produced by the organism itself, 
as in hard muscular work (long marches, athletic games, running 
matches, etc.) these signs again follow. The real reason why 
the signs of a nephritis appear after hard muscular work is be- 
cause the lactic acid produced in the muscles and necessary 
for their contraction is not oxidized as fast as formed. In 
other words under such " normal " circumstances there occurs 
a sufficient accumulation of acid in the body and in the kidney 
specifically to give rise to albumin and casts in the urine if the 
normal supply of oxygen to the tissues is reduced. Under path- 
ological circumstances a reduction in oxygen supply comes to 
pass in heart disease, respiratory disease, the anemias, carbon 
monoxid poisoning, etc., and this explains why albumin, casts, 
etc., appear in such cases. 

Under all these circumstances the original conditions leading 
to the nephritis lie entirely outside the kidney. Direct inter- 



THE ARGUMENT 23 

ference with the oxygen supply to the kidney itself, as through 
pressure upon its blood vessels, arterio-sclerosis, etc., is followed 
by a local production or accumulation of acid in this organ and 
by the signs of nephritis. A final way of causing an abnormal 
production or accumulation of acid is by interfering with the 
power of the kidney to utilize oxygen even though this is supplied 
in sufficient amount. The metallic salts, the alkaloids, the 
anesthetics and other poisons belong to this group. The albu- 
minuria of the newborn and that occasioned by salt starvation 
and excessive consumption of water receive consideration. (See 
pages 488-502.) 

Incidentally, it will be observed that the argument regarding 
the nature and cause of nephritis is much the same as that pre- 
viously given for the nature and cause of oedema. Actually, 
nephritis is in good part an oedema of the kidney. * 

As noted in discussing oedema, other substances besides 
acids, notably the alkalies, urea, pyridin and certain amins 
are capable of increasing the hydration capacity as well as the 
solution of proteins. Since swelling and solution of its proteins 
characterize the nephritic kidney we are not surprised to find 
these same substances capable of inducing a nephritis. In cases 
of alkali poisoning, or when alkali is introduced intravenously 
into animals, all the signs and symptoms of a nephritis develop. 
(See pages 502-504.) 

How now does such a single factor as an abnormal produc- 
tion and accumulation of acid in the kidney lead to the signs and 
symptoms of a nephritis? Acid acting upon protein makes it 
not only swell, but go into solution. The albuminuria of nephritis 
not traceable to gross lesions, as to bleeding, to diapedesis of red 
or to migration of white blood corpuscles, etc., is due to such a 
solution of the kidney proteins in the urine. The relation between 
the so-called swelling and the solution of a protein receives sepa- 
rate consideration. While frequently associated processes, they 
are essentially different. What they seem to represent from a 
theoretical point of view is taken up. (See pages 504-531.) 

Before discussing the mechanism by which each of the dif- 
ferent morphological changes characteristic of nephritis is brought 
about, it is necessary to come to an understanding of what is the 
relation to each other of the different types of nephritis which we 
recognize clinically, and how these are correlated with anatom- 



24 



(EDEMA AND NEPHRITIS 



ical findings. There is only one kind of nephritis, parenchy- 
matous nephritis, but this may affect all the kidney or only 
spots in it. When the former occurs, as after an intoxication 
which involves the whole kidney, we speak of a generalized par- 
enchymatous nephritis. Anatomically this is a large swollen 
kidney, while clinically it is characterized by much albumin, 
many casts and little or no urinary secretion. If the patient 
does not die, one of two things may happen so far as the kidneys 
are concerned. They may recover entirely or pieces in them may 
die, be absorbed, and naught but a scar remain to mark the 
place of death. If this happens a secondarily contracted kidney 
("sniall red kidney") results. As long as one-quarter of the total 
kidney substance is saved it suffices for the patient's needs, and he 
may live and die with this without ever being aware of his state. 
Nor can his state be recognized clinically. (See pages 532-534.) 

Depending upon the factors responsible for it, a spotty paren- 
chymatous nephritis may also recover or the involved areas 
die. If the latter occurs, replacement by connective tissue 
again follows, and the ''small red kidney/' which, as morpholo- 
gists, we call chronic interstitial nephritis, again results. (See 
pages 534-535.) 

The mechanism, however, by which a spotty nephritis is 
brought about is usually totally different from that which brings 
about a generalized nephritis. A poison circulating in the blood 
affects for the most part the whole kidney at once and uniformly. 
For the focal lesions there must be focally acting causes. Most 
commonly these are found in the changes of blood-vessel disease 
which lead to a defective blood supply with destruction and 
death of one piece after another of the kidney. As the con- 
nective tissue which replaces the lost areas has been very gen- 
erally regarded as the cause of the necrosis instead of consequent 
thereupon, these kidneys are called primarily contracted kidneys. 
As the small areas of kidney substance become involved there 
appear a few casts and a little albumin in the urine. But since 
the kidney between these spots is functioning normally and since 
one-quarter of the total kidney substance suffices for all ordinary 
needs, the urinary output in such patients remains normal. As 
will be shown later, the high blood pressure, cardiac hypertrophy, 
etc.. so frequently observed with this type of chronic interstitial 
nephritis, are not the consequences of kidney disease, but ex- 



THE ARGUMENT 



25 



pressions of the vascular disease here held responsible for the 
kidney lesions. (See pages 535-538.) 

Infections of the kidney are not ordinarily considered with 
the nephritides, but they might as well be. In the infections 
the poison is simply produced within the kidney itself instead 
of being carried into it from elsewhere in the body. Depending 
upon the amount of kidney involved, such infections may give 
rise to either local or generalized nephritides, accompanied in 
the former case by few casts, little albumin and a normal water 
output, in the latter by the reverse. (See page 538.) 

The remaining portions of healthy kidney substance consti- 
tuting the small red kidney and anatomically diagnosed as chronic 
interstitial nephritis, whether secondary to a generalized par- 
enchymatous nephritis or consequent upon blood vessel disease, 
may at any time and for various "reasons become the seat of a 
generalized parenchymatous nephritis. Most commonly the heart 
fails. When this happens, the normal or increased urinary output 
with few casts and little albumin gives way to a diminished output 
with many casts and much albumin. (See pages 538-539.) 

The portions of a kidney involved in nephritis show : 

1. An increase in size. 

2. A loss in normal color due to the appearance of granules 
in the affected cells. 

3. The appearance of blood corpuscles extravascularly. 

4. Evidences of a falling apart of the kidney leading to the 
formation of casts. (See pages 539-540.) 

The increase in size is due to a swelling of the kidney colloids 
under the influence of the abnormal production and accumu- 
lation of acid. The change in color is due to the precipitation 
under the same circumstances of a second colloid of the nature of 
casein. The two together constitute " cloudy swelling." (See 
pages 540-554.) 

The bleeding from the kidney in nephritis is in part due to 
rupture of the blood vessels, in part to diapedesis. The mech- 
anism of diapedesis is discussed. The tissues ordinarily are 
sufficiently stiff to prevent the red blood corpuscles from sinking 
into them. After absorbing water under the influence of an acid 
they become less rigid (their viscosity is decreased) and the 
corpuscles are now able to penetrate them. The process of 
diapedesis can be mimicked by allowing mercury drops to 



26 



OEDEMA AND NEPHRITIS 



move in all directions through a solid gelatin. (See pages 555- 
559.) 

When the surface of a fresh kidney is scraped one obtains 
only a granular detritus consisting of broken cells, but if the 
kidney is treated with a dilute acid or is simply subjected to 
the action of such as are produced post-mortem, it falls apart 
into its constituent elements, the cement substance dissolving 
first, while the epithelial cells stick together and slip out of the 
tubules as casts. The casts are originally epithelial, but become 
granular as the action of acid upon them is prolonged. When 
the concentration of the acid is increased the casts become hya- 
line. By proper regulation of acid and salt content the hyaline 
casts may be reconverted into granular casts. The danger is 
pointed out of drawing too large clinical conclusions from the 
character of the casts found in the urine, which within its ordinary 
limits of acidity, salt concentration, etc., can so markedly change 
them. (See pages 560-566.) 

To meet the criticism that the swelling and solution of the body 
proteins as observed in cedema and nephritis cannot occur in the 
living body under the influence of various acids because the body 
cells contain buffer salts (like phosphates and carbonates) experi- 
ments are introduced on the swelling and solution of gelatin and 
fibrin in various so-called buffer mixtures. It is shown that gela- 
tin immersed in different concentrations of the primary, binary 
and ternary salts of phosphoric, citric or carbonic acids swells not 
only with the salt but with its concentration. The absorption of 
water is detailed by gelatin plates lying in phosphate and citrate 
mixtures, varying from the extreme of the pure acid on the one 
side, through the mono-, di- and trisodium salts of these acids to 
pure sodium hydroxid on the other. Irrespective of the manner 
in which these mixtures are prepared (whether by progressive 
substitution of one salt for another through the addition of the 
requisite acid to an alkali, through the addition of alkali to the 
proper acid, through the addition of either acid or alkali to a given 
salt) it is found, when the amount of water absorbed is plotted on 
the vertical and change in composition of the mixture on the 
horizontal, that the result yields a V-shaped or U-shaped curve. 
From a minimal point in the middle of this curve there is a progress- 
ive increase in water absorption to the left or to the right as the 
acid content or alkali content of the mixture is increased. What 



THE ARGUMENT 



27 



has been said of phosphate and citrate mixtures holds also for 
carbonate mixtures. (See pages 567-596.) 

A study of the liquefaction or " solution" of gelatin in these 
same polybasic acids and their salts shows that solid gels may be 
obtained only in the lowermost portions of the V- or U-shaped 
curves, — that this protein, in other words, tends to soften, to 
liquefy and to go into solution as we pass from a middle point in 
these buffer mixtures in the direction of either acid or alkali. 
(See pages 596-602.) 

A study of the swelling of fibrin in polybasic acids and their salts 
brings out the same general truths. The findings taken together 
are held to be applicable to the problem of water absorption by pro- 
toplasm and its " solution" and to sustain the old contention that 
even in the presence of buffer salts there is an increase in water ab- 
sorption (increased turgor or oedema) and an increased tendency to 
go into solution (albuminuria, etc.) with every increase in acid (or 
alkali) content of the protein colloids found in the involved cell, 
organ or organism above a given low point. (See pages 602-614.) 

Many of the clinical manifestations observed in patients 
with kidney disease are considered consequences of the impair- 
ment of kidney function. While there are consequences to loss 
of kidney function, those clinically regarded as such almost 
without exception do not belong in this group. Blood vessel 
disease, high blood pressure and cardiac hypertrophy are not 
secondary to loss of kidney function. The primary disturbance 
in chronic interstitial nephritis associated with vascular disease 
and changes in the heart is the vascular disease, and the changes 
in the kidneys, heart and other organs are secondary to it. This 
can be proved both from clinical observation and experiment. 
The worst cases of nephritis in which there is greatest loss of 
kidney function, as in the toxic nephritides occurring in scarlet 
fever, pregnancy, etc., there is no high blood pressure; nor when 
the kidney substance of animals is experimentally reduced to 
the physiological minimum do vascular disease, high blood pres- 
sure or cardiac hypertrophy develop. The primary change 
being blood vessel disease, it is easily understood why the other 
signs and symptoms must follow. In consequence of the de- 
struction of one piece of kidney after another by the changes 
characteristic of vascular disease as displayed in the small blood 
vessels of this organ with subsequent replacement by scar tissue, 



28 



(EDEMA AND NEPHRITIS 



the kidney undergoes gradual diminution in size. The pieces 
die with the signs characteristic of parenchymatous nephritis, 
but because what remains of the kidney is healthy and but one- 
quarter is necessary to maintain life, patients with this type of 
chronic interstitial nephritis show no change in urinary output. 
(See pages 614-623.) 

The hypertrophy of the heart is not consequent upon loss of 
kidney function, but is the result of a demand for increased work 
and increased power. The source of these demands resides in 
the changes in the blood vessels. Because of their decreased 
caliber an increased force is necessary to drive the blood 
through them, and because they are inelastic the heart is required 
to push the blood through them in the time of a systole alone, 
instead of as ordinarily in the time of a systole, plus a diastole, 
plus a pause. More work is therefore done and in less time. 
In mechanics more work in less time requires a more powerful 
machine, and the hypertrophy of the heart is an expression of 
this law in the body. (See pages 623-625.) 

As it is only through the increased blood pressure that the 
different organs of the body are adequately supplied with blood 
when vascular disease is present, the high blood pressure cannot 
in itself be regarded as something evil, but must be looked upon 
as decidedly good. Except in hemorrhage, treatment which 
merely lowers blood pressure is of no value and often dangerous. 
Because of the weakened blood vessel walls, all those agencies 
which tend to increase blood pressure even in normal individuals 
should be controlled, but beyond this only that therapy has value 
which tries to combat the underlying cause of the increased 
pressure, namely, the vascular disease itself. " Hypertension " 
is not a clinical entity any more than is " fever " or " dropsy " 
and schemes for reducing it which do not consider its underlying 
physiology and pathology are worthless. (See pages 625-626.) 

The oedema observed in some cases of nephritis, particularly 
in the parenchymatous types, is also not secondary to the kidney 
disease. Patients suddenly deprived of their renal function, 
as through accidental removal of an only kidney, or animals 
similarly treated by removal of both kidneys, develop no oedema. 
On the other hand, patients or animals poisoned with any of the 
popular " kidney poisons " like arsenic, salvarsan, uranium, etc., 
develop an oedema in a short time. But the generalized oedema 



THE ARGUMENT 



29 



is not secondary to the kidney disease, but represents in the in- 
volved tissues the same type of change as that which in the kidney 
we call nephritis. (See pages 626-628.) 

Similar clinical observations and experiments prove that 
the headache, vomiting, disturbances of vision, stupor, respira- 
tory changes, coma and death, clinically regarded as signs of a 
"uremia," are not secondary to loss of kidney function. Neph- 
rectomized patients or animals show no such symptoms. The 
alleged "uremic" symptoms are due to cedemas of various portions 
of the central nervous system and are caused by the same agents 
which are inducing the oedema elsewhere in the body, including 
the kidney. (See pages 628-629.) 

A reinterpretation of the clinical manifestations associated 
with nephritis is attempted on the basis of these facts. (See 
pages 629-634.) 

Since vascular disease is regarded as the cause rather than 
the consequence of kidney disease, its etiology is discussed. 
The pathological changes observed in the blood vessels in 
vascular disease are focal in type in even the most advanced 
cases. The whole of the media, or the whole of the intima 
of 'an aorta, for example, is never involved. A generalized 
intoxication cannot, therefore, underlie it. To get the focal 
lesions we must have focal causes, and infectious emboli are 
undoubtedly to be regarded as the underlying cause. The 
emboli lodge in the smaller blood vessels and thus give rise to 
the local necroses observed in the kidney, retina, brain, etc. 
When they lodge in the small blood vessels supplying the coats 
of the larger ones (as in the aorta) the patchy spots of 
softening, absorption, connective tissue overgrowth, and cal- 
cification characteristic of "atheroma" and arteriosclerosis 
follow. On this basis the importance of looking for sources 
of infection in patients with vascular disease is emphasized. 
(See pages 634-636.) 

Disturbances in secretion in nephritis are of two types, those 
affecting the output of water and those affecting the output of 
dissolved substances. (See pages 636-638.) 

The introduction of acid into the kidney by any means what- 
soever is followed by a prompt decrease in urinary secretion 
even to the point of absolute stoppage. The same factor so 
largely responsible for the other signs of nephritis is therefore 



30 



(EDEMA AND NEPHRITIS 



responsible for this also. How this acid works is discussed. 
(See pages 638-640.) 

The changes in the excretion of dissolved substances by the 
kidney must be considered under two headings. The decrease 
in absolute amount put out is secondary to the decrease in total 
amount of water secreted. The change from the normal in the 
relative proportions of the dissolved substances given off is second- 
ary to changes in the solution, adsorption and chemical proper- 
ties of the kidney colloids as affected by the presence in them of 
acid and similarly acting substances. The action of acids in thus 
altering the adsorption properties of protein colloids is illustrated 
by experiments on the taking up and giving off of dyes by fibrin. 
(See pages 640-648.) 

Experiments are now introduced to establish further some 
principles of treatment. As the various salts, including sodium 
chlorid, were found to decrease the swelling and solution of pro- 
teins, it was to be expected, since similar changes characterize 
nephritis, that they would also be able to inhibit or make these 
subside when experimentally induced. Asphyxial nephritis, 
that secondary to intravenous^ injection of acid, and that con- 
sequent upon temporary clamping of the renal artery are studied 
in this regard. The decrease in urinary output, with the appear- 
ance of albumin, blood and casts in such urine as is secreted, 
can be overcome almost entirely if animals rendered nephritic 
by such experimental means are treated with various salts. 
Sodium chlorid is no exception to this rule. (See pages 648- 
665.) 

To meet the objection that such suppression of the signs of 
nephritis can be obtained only in animals, a series of observations 
on the albuminuria consequent upon hard muscular work is 
introduced. When athletes are fed liberally on citrus fruits 
the albuminuria developed is decreased in severity. (See pages 
665-667.) 

Were we to formulate a general rule for the prophylaxis and 
the treatment of nephritis we should evidently have to say that 
this lies in an avoidance and removal as far as possible of every 
condition that favors the abnormal production or accumulation 
of acid in the kidney, or of such other substances which in their 
effects on tissue colloids behave like acid. After this is done, 
attention must be directed to combating the effects of such con- 



THE ARGUMENT 



31 



ditions as cannot be removed. The rule to be followed may 
be summarized in the words : Give alkali, salts and sugar. Con- 
trol the intake of water. The alkali is needed to neutralize the 
acid present in abnormal amount. The salts are indicated, and 
sodium chlorid is no exception, because the changes induced in 
the body colloids by the action of acids upon them are counter- 
acted by adding salt. Dextrose or other carbohydrates are given 
not alone from a chemical point of view, in that an abnormal 
production and accumulation of acid is frequently the consequence 
of carbohydrate starvation, but because the sugars are peculiarly 
powerful in reducing certain types of increased hydration in protein 
not produced by acid. The water intake must be reduced to a 
minimum when tissues are to be dehydrated; it must be increased 
when "free" water is demanded for increase in secretion. (See 
pages 667-669.) 

The importance of the diet in treatment is considered. Foods 
high in the mineral acids or in those organic acids (benzoic, oxalic, 
tartaric, etc.) which cannot be readily oxidized to carbonic acid 
in the body should be avoided unless special pains are taken 
to give with such foods an adequate supply of alkali to neutralize 
these acids. A protein diet yields, after oxidation in the body 
an excess, roughly, of 25 per cent of acid, while a vegetable and 
fruit diet yields under the same circumstances a 25 per cent excess 
of alkali. Hence the advantage of the vegetable diet over the 
meat diet. Practically, however, drastic restrictions in the 
dietary are not to be recommended. It is easier and better for 
the patient to be liberal with the diet, but to protect him against 
the effects of an excess of acid by a continuous feeding of alkali 
to the point where his urine is kept persistently neutral to litmus. 
(See pages 669-674.) 

The question of water consumption in nephritis resolves 
itself into two parts, into the use of water in cases where nephritis 
is likely to arise and into its use in the established case. Normally 
the patient needs water in order to have free water available out 
of which to make urine, and since the development of a nephritis 
depends in the end upon an intoxication, water is needed to reduce 
its concentration, for intoxication depends upon concentration. 
The giving of water does not materially increase the work thrown 
on the heart as generally taught, wherefore heart disease, blood- 
vessel disease, etc., do not by themselves contraindicate its use. 



32 



(EDEMA AND NEPHRITIS 



Neither is there any scientific reason against giving water in chronic 
interstitial nephritis. The objections to the use of water are two: 
first, when the hydration capacity of the body colloids is increased, 
the giving of water makes possible their swelling; second, pure 
water in washing through the kidney washes out not only poison- 
ous substances of which we would be rid, but also salts of various 
kinds which we would keep. To give the organism the benefits 
of water without its accompanying bad effects, we need to give 
along with the water properly chosen salts in sufficient amount. 
(See pages 674-676.) 

The natural and artificial means of establishing and main- 
taining a proper salt concentration in the body are discussed. 
(See pages 676-678.) 

When the gastric route alone does not suffice to get adequate 
amounts of alkali and salt into the organism the rectal or the 
intravenous route may be employed. The formulas of proper 
solutions to use under such circumstances are given. Never 
must alkaline mixtures be used subcutaneously or intramus- 
cularly. (See pages 678-695.) 

The case histories of a series of patients are given and 
commented upon to illustrate the practical use of the prin- 
ciples of treatment outlined in this volume. (See pages 696- 
731.) 

How alkali, salt and dextrose may be used to relieve the 
alleged consequences of kidney disease (" uremia," vomiting of 
central origin, papillo-cedema, etc.) as well as other conditions 
in which an oedema of the affected organs constitutes a charac- 
teristic feature is emphasized. (See pages 731-734.) 

(Edema as an alleged consequence of sodium chlorid reten- 
tion is next discussed. Retention is not due to an inability of 
the kidne\ r to eliminate chlorid, but to change in the (protein) 
colloids of the body, which, under the influence of an abnormal 
production and accumulation of acid, not only swell (become 
cedematous) but at the same time retain more chlorid. Experi- 
ments on gelatin and fibrin are introduced to support this con- 
tention. (See pages 734-738.) 

The generalized oedema so frequently observed as an accom- 
paniment of certain types of kidney disease needs to be treated 
on the same principles as the oedema of the kidney itself. All 
salts are indicated because they decrease this generalized oedema 



THE ARGUMENT 33 

lis they do the swelling of the kidney itself, and sodium chlorid 
is no exception to the rule. (See pages 738-740.) 

The accumulations of fluid in the body cavities in states of 
oedema represent colloid solutions in which the water is largely 
bound to the colloid as hydration water. They are therefore 
absorbed only with difficulty, and this is why when sufficiently 
large in amount they need to be and can be gotten rid of only 
by tapping. How the administration of salt and alkali while 
reducing the oedema of the body tissues generally may increase 
the accumulations of fluid in the cavities is commented upon. 
(See pages 740-743.) 

An effort is made to explain how the salt restriction scheme 
of therapy practiced by many, leads to the good results reported. 
It is not the salt restriction, but the accompanying water re- 
striction that does the work. By sufficiently reducing the intake 
of water we succeed in losing more water (by evaporation, etc.) 
in the unit of time than is taken in, and so all the organs of the 
body dry out. This at times succeeds in breaking into the vicious 
circles established in many organs when once they begin to swell. 
The swelling compresses their blood supply and thus aggravates 
their already precarious state. Dehydration of the organ through 
water starvation may suffice to save it. It is pointed out, how- 
ever, that by obtaining such dehydration through administration 
of properly chosen salts with water instead of through water 
starvation, we gain the advantage for our patient of having water 
available to float off his poisonous products. (See pages 743- 
745.) 

The meaning of the signs and symptoms displayed by patients, 
the victims of nephritis, and their prognostic value are taken up, 
and the correlation between urinary findings and the clinical 
manifestations originating in organs other than the kidney is 
made. (See pages 746-757.) 

The physiological principles to be borne in mind in any at- 
tempt to develop an efficiency test for an organ are considered. 
Because of the great reserve available in nearly all of them they 
continue to show a normal function as long as more than a physio- 
logically necessary minimum remains preserved. Three-quarters 
to seven-eighths of the normal functional capacity of an organ 
may be lost before the organism as a whole shows the effects of 
it or before it can be discovered by functional tests. Even then 



34 



(EDEMA AND NEPHRITIS 



the test must be heightened to the point of straining what re- 
mains before the loss becomes apparent. These considerations 
hold for the kidney. The functional capacity of the kidney is 
best tested by its power to eliminate water. I have never seen 
a kidney that would secrete water which would not also secrete 
all dissolved substances. Tests dependent upon an elimination 
of dissolved substances are fraught with greater possibilities 
for error and are therefore less satisfactory. As long as one- 
quarter (more probably one-eighth) of the total kidney function 
is preserved all such tests yield normal figures. Animals in which 
three-quarters of the total kidney substance has been removed 
excrete water and all dissolved substances as do normal animals. 
When less than one-quarter (or more probably one-eighth) of the 
total kidney substance is functioning a diminished output of 
water and of certain dissolved substances becomes evident, but 
when such extreme states of renal insufficiency are experimentally 
produced or encountered clinically elaborate tests are not neces- 
sary to bring them to light. Efficiency tests are of greatest 
service for the discovery of unilateral kidney lesions. The teach- 
ing that successful prognostications regarding the onset of " ure- 
mia," etc., can be made on the basis of kidney efficiency tests, 
needs to be examined critically, for most of such alleged conse- 
quences of kidney disease are not consequences. (See pages 757- 
765.) 

Since an abnormal production, or accumulation of acid in 
the kidney is so largely responsible for the development of the 
signs and symptoms of nephritis, the importance of following the 
acidity of the urine is emphasized. The meanings of titration 
acidity and of hydrogen ion acidity are defined. The deter- 
mination of either or of both furnishes valuable data in the 
clinical control of every case of nephritis, but neither can alone 
serve as an index to the severity of the intoxication occurring 
in the kidney. How the physician may use simple indicators 
in the urine by way of determining roughly its hydrogen ion 
acidity and the meaning of such determinations is explained. 
(See pages 765-778. 

It is characteristic of animals when subjected to intoxication 
with acid to draw first upon their supply of fixed bases to neutralize 
the acid. When these have been largely exhausted the carnivora 
have a second method of meeting the acid intoxication, namely, 



THE ARGUMENT 



35 



by the production of ammonia. An absolute or relative increase 
in the ammonia output in the urine (or other secretion from the 
body) therefore becomes evidence for and a quantitative guide 
to the degree of acid intoxication. The usefulness of ammonia 
determinations in nephritis is therefore emphasized. (See pages 
778-783.) ~ • 

The section closes by pointing out how a diagnosis of nephri- 
tis has in itself but little meaning, in that after this has been 
made it is ever necessary to say why the nephritis has come to 
pass. As the conditions leading to or likely to lead to the signs 
and symptoms of nephritis are largely known, the great impor- 
tance of prophylactic measures is emphasized. (See pages 
783-792.) 

PART SEVEN 

Glaucoma from a pathological standpoint represents one of 
the local cedemas, and from a clinical point of view all its signs 
and symptoms are referable to the increased intraocular pressure 
resulting from the oedema. An eye becomes glaucomatous 
not because water is forced into it, but because it suffers changes 
which make it suck up an increased amount. The eye is built 
up of a series of colloids which normally have a certain hydration 
capacity. Anything which in the body is capable of increasing 
this hydration capacity leads to a swelling of the eye and con- 
stitutes therefore a cause of glaucoma. As in other forms of 
cedema, evidences may be found in cases of glaucoma for an 
abnormal production or accumulation of acids in the eye and 
of substances which in their action upon colloids behave like 
acids. (See pages 795-797.) 

As the abnormally high hydration of the ocular colloids which 
characterizes glaucoma may be reduced through various salts, 
so can clinical cases of glaucoma be given relief from symptoms 
by the subconjunctival injection of properly selected salts such 
as socuum citrate. (See pages 797-799.) 

The problem of glaucoma and its treatment is identical with 
the problem of nephritis, and exactly as we err in the treatment 
of nephritis when we consider only the kidney, so do we go wrong 
when in glaucoma we consider only the eye. Starvation, an 
excessive protein diet, hard muscular and mental work, excessive 



36 



CEDEMA AND NEPHRITIS 



consumption of sour wines, various intoxications (anesthetics, 
alcohol and arsenic), the infections, the severe anemias, arterio- 
sclerosis, uncompensated heart lesions, exposure to cold, etc., 
are all associated with an abnormal production of acid in the body, 
and constitute in consequence potent factors in the precipitation 
of the glaucomatous attack. These must be recognized and 
removed if we expect the attack to subside. If they cannot be 
removed, then we need to meet their consequences, and since 
we deal here with factors affecting the whole patient we must 
treat him. For this reason alkali, salts, dextrose and a controlled 
water intake are indicated in the same way and for the same 
reasons as in nephritis. (See pages 799-802.) 

The prognosis in glaucoma depends entirely upon the nature 
of the factors appearing in its etiology. A diagnosis of "glau- 
coma" is as complete as one of "dropsy." When the swelling 
is due to a transient intoxication, or to temporarily acting 
infections, mere reduction of tension by any means whatsoever, 
whether surgical or medical, can easily lead to brilliant results 
and permanent relief, but when irremovable causes such as 
blood vessel disease are responsible for the glaucoma — by far its 
commonest cause in older individuals — no scheme of treatment 
which ignores the blood vessel disease and which merely centers 
attention upon the eye can yield anything but temporary and 
ultimately disappointing results. (See pages 802-806.) 

The nature of the corneal opacities and the cloudiness of the 
clear media so often observed in glaucoma and certain other 
pathological states is discussed. They are not due to oedema, 
but represent precipitations of protein of the nature of casein. 
The " clouding " thus caused by the precipitation of one type 
of colloid while another is swelling, together make glaucoma 
but another example of the widely observed " cloudy swelling" 
of the pathologists. (See pages 806-810.) 

A paragraph asking that those who feel tempted to make 
clinical use of any of the therapeutic methods discussed in the 
volume feel tempted also to study the scientific principles upon 
which they are based in order that misunderstanding and dis- 
appointment through improper application of the suggested 
remedial measures may be prevented, closes the volume. (See 
pages 810-811.) 



THE ARGUMENT 



37 



PART EIGHT 

The importance of foci of infection in and about the body for 
the production of the signs and symptoms of nephritis and its 
complications leads to a discussion of the general pathology and 
bacteriology of focal infection. To illustrate what needs to be 
done clinically for the control of all such points of infection, the 
problem of infection in and about the teeth is taken up in detail. 
The significance of the teeth as living tissues is stressed, the 
physiology of their maintenance is discussed .and the pathology of 
their infection is reduced to that of the general pathology of infec- 
tion in bones and joints. On such basis the principles are then 
enunciated which are considered the right ones for their proper 
medical and surgical care. (See pages 815-851.) 

A clinical lecture is set down to illustrate how in practice the 
concepts of the nature and the cause of nephritis as set forth in 
this volume may be used for the classification, diagnosis, prognosis 
and treatment of patients afflicted with kidney disease and its 
alleged consequences. (See pages 852-892.) 



PART TWO 



ABSORPTION AND SECRETION IN INDIVIDUAL CELLS 
AND TISSUES 



PART TWO 



ABSORPTION AND SECRETION IN INDIVIDUAL CELLS 
AND TISSUES 



I 

THE PROBLEM 

When, in the routine of our day's work, we are brought face 
to face with so practical a matter as the treatment of a patient 
suffering with glaucoma, or from the convulsions of uremia, 
or from an anuria, our behavior, if it is not a blind following of 
empirically transmitted teachings, is determined by what we think 
of the nature and the cause of these deviations from the normal. 
In good part we deal in these illustrations with an oedema of 
the affected organs — of the eye, of the brain, of the kidney — 
and so our treatment becomes but a specialized expression of 
what we think regarding the nature and cause of cedema in 
general. 

But this problem of cedema — the problem of the presence 
of abnormally large amounts of water in tissues and tissue spaces 
— is in itself only a phase of a still greater problem: Why does 
protoplasm hold any water at all, and why does it hold under 
normal circumstances so nearly constant an amount? 

It is easily seen why an interest in cedema or in such special 
expressions thereof as glaucoma, uremia or nephritis should have 
overshadowed the greater and really simpler problem, for all 
these have a human interest that is entirely lacking to the ques- 
tion of why protoplasm generally holds water. That attempts 
should in consequence have been made to answer the question 
of cedema first is not surprising. The ways and means adopted 

41 



42 



(EDEMA AND NEPHRITIS 



may, however, well serve as an example of the short-cut methods 
which clinicians and pathologists have only too often adopted 
in order to obtain light, and with disastrous results. Since oedema 
constitutes a pathological state of interest chiefly in man, various 
hypotheses were formulated to account for the condition on the 
basis of his complex anatomy — such, for instance, as his blood 
and lymph circulatory systems; and when experiments on the 
higher animals failed to bring the corroborating evidence which 
should convert the shadowy hypothesis into the healthy theory, 
recourse was had to the still more shadowy properties of " living " 
cells. To this day the accepted explanation of oedema remains 
an ill-defined mixture of the physical concepts of pressure and 
filtration with the mysterious forces of " living" matter. 

A little thought will show that variations in the amount of 
water held by cells and tissues occur in a great variety of animals 
and plants. To cite but a single example, and one common 
to both plants and animals, mention may be made of the long 
studied phenomena of normal, increased and decreased water 
content in cells which are discussed under the terms turgor 
plasmoptysis and plasmolysis. Isolated animal and plant cells 
have normally a certain water content. Under a variety of 
circumstances they may be made to absorb more. These are 
" cedemas " as true as any ever observed in man, or produced 
experimentally in dog or rabbit. Such reflection should by 
itself have created suspicion against any conception of oedema 
which demands for its production circulatory systems or any 
structures not common to all protoplasm, vegetable as well as 
animal. 

It will not seem strange therefore that the best contributions 
toward the solution of the problem of the ways and means by 
which cells and tissues absorb water have in recent years really 
come through the plant physiologists. Not led into erroneous 
paths through the presence of circulatory systems at all similar 
to those found in the higher animals, the plant physiologists 
early sought the explanation of the variations in the amount of 
water held by the plant tissues in the cells themselves. As we 
shall see shortly, this is where the problem belongs, and the 
attempts of later years to make differences in osmotic pressure 
responsible for the movement and storage of water in animal 
cells as well as in plant cells under normal and pathological con- 



ABSORPTION, SECRETION— CELLS AND TISSUES 43 



ditions cannot be too highly commended. While the theory 
of osmotic pressure is incapable of accounting for more than a 
very small portion of the phenomena observed — even in plants — 
the great value of an attempt to explain variations in the water 
content of animal and plant tissues on a healthy physico-chemical 
basis cannot be questioned. 

To a consideration of the various hypotheses and theories 
that have been proposed to account for the normal water con- 
tent of cells and for the abnormally high water content which 
the plant physiologists discuss under plasmoptysis, the path- 
ologists under oedema, the clinicians under a variety of terms, 
we shall have occasion to return later. Here we would only 
emphasize the fact that all these diversified phenomena bear a 
close relation to each other and need to be discussed together. 
The clinician meeting his medical problem has common interest 
with the pathologist; the pathologist in turn can discuss his 
more abstract notions of cedema only as he considers the physi- 
ologist and his ideas of normal water absorption. This will 
explain why we need in this volume to begin with a discussion 
of fundamental physiological principles. And at all times sub- 
sequently must we find it easy to pass from the extremes of 
pathology back to physiology, or vice versa. 

The unit for consideration in physiology, and so in pathology 
and applied medicine, remains the cell. As practical men we 
are likely to lose sight of this fact or to take exception to it, yet 
the most practical will heed the physiology of the individual 
cell most. Even the highly specialized functions of groups of 
cells or of organs in a complex individual rarely represent more 
than exaggerations of functions common to all cells. This is 
why this volume begins with and constantly reverts to the be- 
havior of the individual cell. To be familiar with the effect of 
various external conditions upon the general behavior of the 
individual cell is to be familiar with the behavior of these same 
conditions upon groups of cells. When such groups of cells (an 
organ) are part of and determine the behavior of yet other groups 
of cells in a complex organism, familiarity with the action of these 
external conditions upon the isolated groups of cells becomes 
synonymous with a knowledge of the action of these external 
conditions upon the organism as a whole. An understanding 
of the most specialized therapeutic procedure is almost invariably 



44 



(EDEMA AND NEPHRITIS 



dependent upon such a knowledge of the cell. We shall find 
many an illustration of this as we proceed. 

With this let us turn to our specific problem .of water absorption 
by the living cell under physiological and pathological circum- 
stances. Since I consider the colloids of the tissues and their 
state as of chief importance in this matter, a review of the prop- 
erties of colloids with particular reference to their behavior 
toward water is first in order. 



II 

THE ABSORPTION OF WATER BY COLLOIDS 

1. Remarks on Colloids: Nomenclature 

While theories regarding the nature of the colloid state do not 
in any way affect the argument of the succeeding pages, brief 
reference to them as evolved by the work of various students of 
the problem during the past several decades may help to clarify 
what must otherwise be carried in the mind in more nebulous form. 1 

§ i 

It is now more than fifty years since Thomas Graham 2 recog- 
nized that chemical substances differ greatly in the rate with which 
they diffuse through solvents of various kinds. On the basis of 
this observation he made a distinction between those which diffuse 
but slowly and those which diffuse rapidly. As the former are 
for the most part amorphous, and since ordinary glue (koAAci) is 
an example of this class, he called them colloids. The group that 
diffuse readily he called crystalloids, for such beautifully crystal- 

1 Surveys of the field of colloid chemistry are now available in several 
splendid texts which must be consulted for details beyond the confines of 
this volume See especially Wolfgang Ostwald: Theoretical and Applied 
Colloid Chemistry, translated by Martin H. Fischer, New York (1917); 
Handbook of Colloid Chemistry, translated by Martin H. Fischer, 2d Ed., 
Phila. (1919); Richard Zsigmondy and Ellwood B. Spear: Chemistry of 
Colloids, New York (1917); Jerome Alexander: Colloid Chemistry, New 
York (1919); H. Bechhold: Colloids in Biology and Medicine, translated 
by J. G. M. Bullowa, New York (1919). 

2 Thomas Graham: Phil. Trans., 183 (1861); Liebig's Annalen, 121, 13 
(1862). 



ABSORPTION, SECRETION— CELLS AND TISSUES 45 



line substances as cane sugar, ordinary salt and urea are found in 
it. Graham noted also a second difference between his colloids 
and the crystalloids. While the latter, when enclosed in a fish 
bladder or parchment paper tube passed readily through such 
structures into a surrounding medium of, say, pure water, the 
colloids did not do so. This is the principle which underlies 
dialysis. When, in other words, a mixture of colloids and crystal- 
loids were together subjected to dialysis only the crystalloids dif- 
fused out of the mixture and through the dialyzing membrane, — 
there occurred a separation or what Graham termed an " analysis" 
of the mixture by dialysis. 

Since Graham's studies we have become familiar with further 
characteristics of colloids and crystalloids. Crystalloids are 
ordinarily stated to form "true" solutions. This means that when 
such a substance as common salt is dissolved in water there is 
nothing about the finished mixture which does not show it to be 
homogeneous. Light waves, for example, pass through it as though 
it were of exactly the same composition throughout. The typical 
colloids behave in quite a different fashion. They are said to form 
"pseudo-solutions" and even relatively superficial tests may suffice 
to show that they are heterogeneous in composition. While still 
"solutions" in ordinary parlance they are less apt, when viewed 
by ordinary light, to be "clear." They are commonly opalescent 
or distinctly turbid, indicating that light waves no longer pass 
through them without encountering greater difficulties in some 
spots than in others. More technically put, there are existent in 
these pseudo-solutions phases possessed of different properties. 
But such characteristics tend to put these systems into the physi- 
cist's realm of the "suspensions." 

Of other distinctions between colloids and crystalloids modern 
analysis has shown that solutions of crystalloids show an osmotic 
pressure, a lowering of the freezing point and an elevation of th3 
boiling point proportional to the number of particles of dissolved 
substance contained in the unit volume of solvent. The most 
typical colloids show practically no such relations. These differ- 
ences are commonly paralleled with the molecular weights of the 
substances representative of each of the two groups, which in the 
case of the most pronouncedly colloid bodies is often said to be 
measurable in thousands, while a hundred or two covers the weight 
of even the more complex organic crystalloids. 



46 



(EDEMA AND NEPHRITIS 



Such facts made it long appear as though colloids might be 
correctly defined as pseudo-solutions or suspensions of amorphous, 
non-diffusing, non-dialyzing materials of high molecular weight, 
showing little inclination to yield systems governed by the ordinary 
laws of dilute solutions. When systems were encountered which 
did show such behavior we did in fact usually find ourselves face 
to face with colloids and yet what has been written is not sufficient 
to cover all cases. All the distinctions thus far drawn between 
colloids and crystalloids are really attempts at the classification of 
substances, and several and serious attempts were actually made to 
catalog compounds as either colloids or crystalloids. But time 
showed their inadequacy, for substances definitely colloid under 
certain circumstances could, under others, be obtained in crystal- 
loid form and vice versa. Hemoglobin or albumin, for example, 
ordinarily characteristically colloid were obtained in crystalline 
form while such comparatively simple bodies as silicic and tung- 
stic acids and the various metal hydroxids, were found in the 
group of the most representative colloids. Such facts sufficed to 
show that no hard and fast line could be drawn between the colloids 
and the crystalloids. In fact, as colloid-chemical investigation 
proceeded it became more and more evident that any substance 
could be obtained in colloid form. 1 This discovery necessitated a 
complete change in our concept of the term. Colloids are no 
longer to be thought of as substances but as materials in a certain 
state; the term colloid is not a noun but an adjective. 

Modern study has shown that colloid chemistry occupies the 
middle ground between that of the chemist who deals with sub- 
stances in true solution and that of the physicist who works with 
matter in mass, as in coarse suspensions. A solution, to the 
chemist, is a mixture of one material in a second with the degree of 
subdivision of the first in the second carried so far as to yield only 
particles of molecular or smaller size (the molecules, ions or elec- 
trons found in an ordinary "true" solution of sand in water, for 
example). On the other hand, a suspension, to the physicist, is a 
mixture in which he distinguishes fairly easily, as by optical 
methods, the subdivided material from that in which it is sub- 
divided. He is able, for instance, not only to recognize microscop- 
ically the particles of sand in a sand-water mixture but he can 

1 P. P. von Weimarn: KoUoid-Zeitschr., 2, 76 (1907); ibid., 5, 62, 117, 
151, 212 (1909). 



ABSORPTION, SECRETION— CELLS AND TISSUES 47 

separate these from the water by allowing the mixture to stand. 
Colloid solutions lie between these two extremes. They are sub- 
divisions or dispersions of one material in a second with the degree 
of subdivision coarser than molecular and yet not so coarse as to lie 
within the physical realm of easy microscopic visibility. While 
the limits chosen are arbitrary (since there exist no abrupt transitions 
from true solutions to colloids, nor from these to the suspensions) 
the subdivided materials have on this basis a diameter coarser than 
1/1000000 millimeter and finer than 1/10000 millimeter. 1 

This relationship of colloid chemistry to the realms of the molec- 
ular chemist and of the physicist may be illustrated in diagram- 
matic fashion by such a drawing as Fig. 1. The shaded fragment of 
a circle marked A is representative of a micrococcus. Though on 
the edge of easy microscopic visibility it is nevertheless very coarse 
as compared with even the coarsest particles observable in a 
colloid solution. The circles marked B (drawn to the same scale) 
illustrate the size of particles of colloid gold which are falling out of 
' solution" and which are therefore approaching the realm of the 
physicist and his coarse suspensions. The smaller circles in the 
region marked colloid show the size of particles which remain sus- 
pended. While the larger of these cannot be seen as separate 
particles with the ordinary microscope they can still be recognized 
ultramicroscopically. The smallest, however, escape even such 
analysis and need to be demonstrated by still subtler means. 
The particles marked C are of a diameter which has been calculated 
as correct for the largest molecules. On the scale chosen for the 
diagram these circles might represent hemoglobin molecules. But 
hemoglobin, it will be remembered, was the substance about which 
there was dispute above as to whether, on solution in water, it 
yielded a "true" solution or not. Its position on the crossing line 
from the colloid solutions to the "true" or molecular solutions 
shows why this is the case. The coarser black dots in the realm 
marked molecular illustrate the calculated size of chloroform 
molecules; the fine black dots that of hydrogen molecules. Obvi- 
ously the molecular fragments which are known as ions, atoms and 
electrons must lie still further to the right in the general diagram. 

1 See Richard Zsigmondy: Zur Erkermtnis der Kolloide, 122, Jena (1905) ; 
Richard Zsigmondy and E. B. Spear: Chemistry of Colloids, 19, New York 
(1917); Wolfgang Ostwald: Kolloid-Zeitschr., 1, 291 (1907); Theoretical 
and Applied Colloid Chemistry, translated by Martin H. Fischer, 17-21, 
New York (1917). 



48 



(EDEMA AND NEPHRITIS 



This definition of the colloids as divided or dispersed systems 
with the dispersed particles possessed of certain sizes has, however, 



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necessitated and brought with it a widening of our whole point of 
view regarding such systems. The general argument as outlined 
above has been illustrated by referring to quartz subdivided in 
water or metallic gold in water, in other words, by systems repre- 



ABSORPTION, SECRETION— CELLS AND TISSUES 49 



sen ted by the dispersion of a solid in a liquid. It is obvious, how- 
ever, that from the three physical states of matter, gaseous, 
liquid and solid, many other such "dispersoids" may be com- 
pounded and as follows: 1 

gas in gas gas in liquid (foam) gas in solid (meer- 

schaum) 

liquid in gas (steam) liquid in liquid (emulsion) liquid in solid (opal) 
solid in gas (smoke) solid in liquid (suspension) solid in solid (certain 

semi-precious stones) 

Whenever a material in any one of the three physical states 
may be thus subdivided in any second and this with a degree of 
dispersion which is coarser than molecular and not yet so coarse 
as to come within the realm studied by the physicist we are face 
to face with a colloid system. Of the nine possible combinations 
listed above, eight have been realized in colloid form (the disper- 
sion of a gas within a gas being possible only in molecular or 
supermolecular form). Familiar illustrations of the types of 
systems resulting when matter in one form is dispersed in any 
other, are given in parentheses after the classifications. While 
illustrations of each of the systems may be found in biological 
material under various physiological and pathological circum- 
stances those of greatest importance consist of mixtures of liquid 
with liquid and of solid with liquid. In the future therefore when 
unmodified reference is made to a colloid or a colloid system those 
which come under these chief heads are the ones generally held in 
mind. 

§ 2 

Long before the definition of the colloid state had attained the 
precision outlined in the above paragraphs it was noted that indis- 
putably colloid systems differed sharply among themselves in 
their characteristics. The first to try to systematize these differ- 
ences was A. A/Noyes, 2 who early distinguished between those 
colloids which are 'Viscous, gelatinizing and not readily coagulated 
by salts" and those which are "non-viscous, non-gelatinizing and 
readily coagulated by salts." To the former belong, for example, 

Wolfgang Ostwald: Kolloid-Zeitschr., 1, 291 and 331 (1907); Theo- 
retical and Applied Colloid Chemistry, translated by Martin H. Fischer, 
40, New York (1917) ; Handbook of Colloid Chemistry, translated by Martin 
H. Fischer, 2d Ed., 42, Phila. (1919). 

2 A. A. Noyes: Jour. Am. Chem. Soc, 27, 85 (1905.) 



50 



OEDEMA AND NEPHRITIS 



the colloid solutions of gelatin, soap or dextrin in water, while 
with the latter may be mentioned the colloid solutions of gold and 
quartz in water, already touched upon above. 

The essential difference between the two groups resides in the rela- 
tion which the colloidally dispersed material bears to the solvent. 
This relationship is close in the case of the colloids of the first- 
named type and largely absent in the case of the second. For this 
reason the former are also known as lyophilic colloids, or, when 
water is the solvent, hydrophilic colloids; the latter as lyophobic 
or hydrophobic colloids (J. Perrin 1 and H. Freundlich 2 ). 

Wolfgang Ostwald 3 who has done so much for the proper 
definition and classification of the colloids distinguishes between 
those which are produced when a liquid is dispersed in a liquid 
(the emulsion colloids or emulsoids) and those produced when a 
solid is divided into a liquid (the suspension colloids or suspen- 
soids). Because it is harder to separate a liquid from a liquid 
than a solid from a liquid, a system built up of the former will 
show a greater viscosity, stability, etc., than a system of the second 
type. The attempt has often been made to make the emulsion 
colloids of Ostwald synonymous with Noyes' first group or 
Perrin 's hydrophilic colloids and the suspension colloids of Ost- 
wald with No yes' second group and Perrin 's hydrophobic 
colloids. Ostwald 4 has himself emphasized the error of this. 

Systems of the undoubted composition liquid plus liquid are 
not always lyophilic and systems of the composition solid plus 
liquid are not always -lyophobic. Liquid fat, for example, sub- 
divided in water yields a lyophobic system, while solid sodium 
stearate in water, alcohol or aldehyd yields a lyophilic colloid. 
A lyophobic colloid results whenever the colloidally dispersed phase 
is not a solvent for the solvent; a lyophilic colloid when the dispersed 
material is such a solvent. Because fat is not a solvent for water 
the emuJsification of liquid fat in water yields only a hydrophobic 
system; but because water is soluble in soap (even such a solid 

1 J. Perrin: Journal de Chimie Physique, 3, 84 (1905). 
2 H. Freundlich: Kolloid-Zeitschr., 3, 80 (1908); Kapillarchemie, 309, 
Leipzig, (1909). 

3 Wolfgang Ostwald: Kolloid-Zeitschr., 1, 291 and 331 (1907); Theo- 
retical and Applied Colloid Chemistry, translated by Martin H. Fischer, 
40, New York (1917); Handbook of Colloid Chemistry, translated by Martin 
H. Fischer, 2d Ed., 42, Phila. (1919). 

4 Wolfgang Ostwald: Kolloid-Zeitschr., 11, 230 (1912), 



ABSORPTION, SECRETION— CELLS AND TISSUES 51 



soap as sodium stearate) a mixture of this with water yields a 
hydrophilic system. As the study of the lyophilic colloid systems 
from this point of view serves also to make clear certain of their 
other properties some illustrative facts taken from the colloid 
behavior of the soaps 1 may advantageously be introduced at 
this point. The discussion of the soaps from such a colloid- 
chemical point of view is particularly apt. First, they are typic- 
ally lyophilic (hydrophilic) colloid systems and it is these which 
are of greatest biological importance (fibrin, gelatin, glue, starch, 
glycogen, dextrin, vegetable fibers, albumin, agar-agar, certain 
lipoids, etc., being all hydrophilic colloids); second, the soaps as 
salts of the fatty acids are the chemical analogs of the salts of 
the polymerized amino- (fatty) acids (the proteins) which consti- 
tute living matter. 

§ 3 

When a neutral soap like sodium oleate or sodium stearate is 
mixed with a limited volume of water (a 30 per cent " solution " 
of the former or a 10 per cent " solution " of the latter) and the 
mixture is brought to the temperature of a boiling water bath 
the whole yields a homogeneous solution. The water-like liquid 
shows all the properties characteristic of the " true " solutions 
like a normal osmotic pressure, electrical conductivity, etc. 
When now the temperature is allowed to fall (say to room 
temperature) the mixture becomes in both instances opalescent, 
increases enormously in viscosity and finally sets into a semi- 
solid or solid gel. With fall in temperature there has occurred, 
in other words, transformation to a typical lyophilic colloid 
system. 

When now one tries to state in the simplest possible terms what 
it is that has happened when such a definite mixture of soap and 
water, which is a mobile liquid at the temperature of boiling 
water, is seen to set into a dry, solid mass as its temperature is 
reduced, it seems easiest to think of the whole as a change from 
what is, at the higher temperature, essentially a solution 2 of soap 

1 Martin H. Fischer and Marian O. Hooker: Science, 48, 143 (1918); 
ibid., 49, 615 (1919); Chem. Engineer, 27, 155, 184, 223, 253, 271 (1919). 

2 We are not unaware that the concept "solution" needs itself to be de- 
fined. While the field of " solution " constitutes slippery ground, we accept, for 
pragmatic reasons, as characteristic of the "true" solutions the teachings of 
Wolfgang Pstwald and P.P. von Weimarn who define such as dispersions of 



52 



(EDEMA AND NEPHRITIS 



in water to that which is, at the lower temperature, a solution of 
water in soap. 1 Between these extremes and as determined by 
the temperature and by the relative concentration of soap and of 
water we get various mixtures of solvated soap in soap-water or 
of soap-water in solvated soap. The situation in the case of the 
soaps in the presence of limited volumes of water is identical, in 
other words, with the changes which may be seen in mutually 
soluble systems of the type phenol/water, ether/water or protein/ 
water as studied by J. Friedlander, 2 V. Rothmund, 3 W. B. 
Hardy, 4 Wolfgang Ostwald 5 and their various followers. 

The behavior of the mutually soluble system phenol/ water 
(which is considered particularly apt in the matter of understand- 
ing the colloid behavior of the system soap/water) is shown in 
Fig. 2. The bottle on the extreme left contains phenol only (which 
like any " pure" soap is a crystalline mass at the proper tempera- 
ture). The succeeding bottles contain the same weight of phenol 
plus gradually increasing amounts of water. As more and more 

A in B with the degree of subdivision measurable in molecular or smaller 
values. To express the matter in the terms of A. P. Mathews, we may say 
that A is dissolved in B or vice versa when the solvent has overcome the 
cohesive forces of the dissolved substances. As Mathews has shown, the 
forces of cohesion operate within molecular dimensions. To judge from our 
own impressions as gained by study of such systems as the chemist would 
call "concentrated solutions" we are of the opinion that " solution" means 
in most instances union of solvent with the dissolved material and vice 
versa. Such union is indisputable and attains enormous values in the case 
of the concentrated solutions. That it is ignored or has only small value 
assigned to it in the case of the standard "dilute" solutions is only because 
their general properties are dominated by the large excess of free "solvent" 
present. 

1 The distinction between these two types is not an academic one, as 
witness the differences in reaction of the two systems to such an indicator as 
phenolphthalein. A chemically neutral soap like sodium oleate, palmitate 
or stearate when dissolved in water will turn this indicator a bright red. 
When, however, the water is dissolved in the soap the indicator remains 
colorless. See page 775 or Martin H.Fischer: Chem. Engineer, 27,271 
(1919). Protoplasm is generally regarded as a solution of the protoplasmic 
substances in water; it is almost exactly the reverse, namely, protoplasmic 
substance which has dissolved a certain amount of water. 

2 J. Friedlander: Zeitschr. f. physik. Chemie, 38, 430 (1901). 

3 V. Rothmund: Zeitschr. f. physik. Chem., 63, 54 (1908). 

4 W. B. Hardy: Jour. Physiol., 24, 158 (1899); Zeitschr. f. physik. Chem., 
33, 326 (1900). 

5 Wolfgang Ostwald: Kolloid-Zeitschr., 1, 335 (1907); Theoretical and 
Applied Colloid Chemistry, translated by Martin H. Fischer, 89, New 
York (1917). 



ABSORPTION, SECRETION— CELLS AND TISSUES 53 



water is added the phenol fails to crystallize; up to and including 
the sixth bottle from the left, only " solutions " are obtained but 




these are solutions of water in phenol. The seventh bottle shows 
two layers; below, one of phenol saturated with water, above, a 



54 



(EDEMA AND NEPHRITIS 



solution of phenol in water. With further additions of water the 
later type of solution grows at the expense of the former until, 
finally, in the bottle second from the extreme right of the series 
nothing but a solution of phenol in water remains. 1 

Of importance for our further discussion is, first, the existence 
of the two types of solution, that of water in phenol and that of 
phenol in water. The physical constants of these two solutions 
are totally different and they behave differently, too, toward 
changes in external conditions like temperature or various added 
substances (acids, bases, salts, indicators, etc.). When a little 
methylene blue or malachite green, for example, is added to such a 
mixture as is represented in the seventh or eighth bottle of the 
series, the watered phenol phase stains deeply; while the phenol- 
ated water remains clear. A second point of importance is the 
behavior of such a system when subjected to increases or decreases 
in temperature. When the temperature is raised the watered- 
phenol phase goes over and into solution in the phenolated-water 
phase. It is characteristic of liquids, when their temperature is 
being lowered, to show a progressive increase in viscosity. The 
warmed solution of phenol-in-water also shows such a progressive 
increase in viscosity as its temperature is lowered, but, as first 
noted by Friedlander and Rothmund, this progressive increase 
shows a sharp break as soon as the critical temperature is reached, 
at which the phenol begins to separate out. This break expresses 
itself as a sharp rise in viscosity which increases for a time and 
then falls off again, so that with further lowering of temperature 
a viscosity curve more like the original "normal" is again obtained. 

We are indebted to Wolfgang Ostwald for pointing out 
that, in this critical zone during which the phenol /water system is 
opalescent and shows an abnormally high viscosity we are in reality 
dealing with a colloid system (consisting of watered-phenol dispersed 
in phenolated-water). 

Turning now to the study of the mechanism employed for the 
production of the soap colloid systems, it is evident that they are 

1 In analogy to what happens in the "salting out" of colloids it is well to 
explain the nature of the contents of the right-hand bottle in the series. 
This was originally nothing but a solution of phenol in water, but through 
the addition of ordinary table salt the phenol was "salted out" so that now 
a phenol phase with some water dissolved in it (analogous to a salted-out 
colloid of the biochemists or colloid chemists) is seen floating at the surface 
of the liquid in the bottle. 



ABSORPTION, SECRETION— CELLS AND TISSUES 55 



formed by " dissolving " a unit weight of soap in a definite volume 
of water at a rather high temperature. In the accepted parlance, 
it may be said that through such increase in temperature the sol- 
ubility of the soap in the water is tremendously increased. 

To illustrate in rather crude fashion the effects of a lowering of 
temperature, Fig. 3 (Diagrams A and B) is introduced. They 
show the results when any two mutually soluble substances, like 
water and soap, are mixed together. When the soap is readily 
soluble in the water and the concentration is rightly chosen there 
results a true solution at the higher temperature. This matter 
is represented by the region marked A in the diagrams (the soap 
is dispersed molecularly or ionically in the solvent). If, now, the 
temperature is lowered, the solubility of the soap in the water is 
decreased. As the saturation point for the lower temperature is 
attained, the soap particles assume not only molecular size but 
more than molecular size. By definition, therefore, we approach 
with falling temperature the realm of the colloids, or that of dis- 
persions of one material in a second with the degree of dispersion 
showing dimensions greater than the molecular. The gradual 
increase in the size of the soap particles (or increase in their num- 
ber) with lowering of the temperature is represented by the 
regions B, C, D, E and F. 

Thus far has been explained merely the production of a colloid 
system by the ordinary process of bringing about supersaturation 
and an agglomeration of particles previously more highly dispersed. 
It is obvious that such agglomeration may yield either a so-called 
lyophobic or lyophilic colloid (or, depending upon the solid or 
liquid nature of the separating phase, a suspension or an emulsion 
colloid). The lyophobic colloid results when the solvent is not soluble, 
the lyophilic when the solvent is soluble in the precipitating phase. 
When soap falls out of solution from such a solvent as allyl 
alcohol the former of these possibilities is satisfied; when it falls 
out, as in our illustration, from water, the latter is satisfied. The 
black circles or crystal clusters in the diagrams of Fig. 3 represent 
more, therefore, in the latter instance than precipitates of pure 
soap; they are this, plus a certain amount of the water (or other 
" solvent ") dissolved in them. 

At a sufficiently low temperature the soap aggregates will 
have become so large or so numerous as to touch and coalesce. 
If this process continues to a sufficient extent the system will 



56 



OEDEMA AND NEPHRITIS 



ultimately rep- 
resent in essence 
nothing but soap 
in which the pre- 
vious " solvent" 
is now dissolved. 
Diagrammatic- 
ally this situa- 
tion is represent- 
ed by the zones 
Z of Fig. 3. 

A glance at 
Fig. 3 shows, 
however, that 
between the up- 
per extreme (A) 
of a solution of 
the soap in the 
solvent and the 
lower extreme 
(Z) of a solution 
of the solvent 
in the soap, there 
exist two main 
zones of mixed 
systems, — one 
below the upper 
(B, C, D and E) 
consisting of a 
dispersion of sol- 
vated - soap in 
the soaped-sol- 
vent, and a sec- 
ond above the 
lower (F, X, W, 
andF) consisting 
of soaped - sol- 
vent in the 
solvated-soap. 
These two mixed 



SOAP 



WATER 




WATER IN SOAP 

Figure 3 (Diagram A). 



ABSORPTION, SECRETION— CELLS AND TISSUES 



57 



SOAP IN WATER 



B 



******** 

******** 
******** 
******** 

* 4fr * * * * 
% % * * * % % 
% % % ^ % % % 

Sfe. 4lfc. ^ -^fe 

* * W W i& 

****** 



* * * 

* * * 

* * * 



* * 

* * 



***** 

* * * % % 
** % % * % 

* * ■* % * 

% 

***** 
****** 
****** 
****** 

/TV /f\ /p? 




vm-m 
MIC 



% * * 

ift # * 



•#§ 

41 

■# « * 
»• * * 

* * 4 

J* 



* # * i 

#, * * Tjj 

* ■* 

* * * * ;i 



u 



w 



WATER IN SOAP 

Figure 3 (Diagram B\ 



systems (if the soap 
is liquid) are in 
essence emulsions, 
but of opposite type 
and as such (even 
when of the same 
quantitative chem- 
ical constitution) 
are possessed of 
totally different 
physical properties. 
The former corre- 
sponds, for exam- 
ple, to an emulsion 
of oil-in-water, the 
second to one of 
water-in-oil, and as 
the former (as il- 
lustrated by milk) 
will mix with water, 
wet paper and show 
a certain viscosity 
value, the latter (as 
illustrated by but- 
ter) will mix only 
with oil, will grease 
paper and show an 
entirely different 
viscosity. 1 

Returning to 
the lyophilic soaps 
and the diagrams, 
it is obvious that 



x See in t this con- 
nection Martin H. 
Fischer and Marian 
O. Hooker: Science, 
43, 468 (1916); Fats 
and Fatty Degenera- 
tion, 20, New York 
(1917). 



58 



(EDEMA AND NEPHRITIS 



as we descend with lowering of temperature from the region 
A, we pass in the regions B, C and D through increasingly viscid 
liquid colloid " solutions " (so-called sols) but all of them emulsions 
of the type solvated-soap in soap-water. In the region E, the 
particles of solvated soap almost touch and here the highest (liquid) 
viscosity is obtained. In F they do touch and now form a con- 
tinuous external phase. At this point we change to the opposite 
type of emulsion (to one of soap-water in solvated-soap) and the 
previously liquid colloid becomes solid. As ordinarily put, the 
mixture gels. 

It is of interest next to emphasize how this concept of the 
changes which a soap/ water system suffers in passing from a liquid 
sol to a dry gel may help to explain various of the " strange " 
characteristics of colloid systems. 

A first question under this heading is that of the nature of 
, hysteresis, more particularly that observed when a colloid is sub- 
jected to changes in temperature. The importance of the thermal 
history of a colloid system is constantly stressed. It is generally 
true of the lyophilic colloids that, when subjected to heat manip- 
ulation, they tend to hold fast to the characteristics of their pre- 
vious states. A colloid on cooling, for example, first sets at 
a certain temperature; yet the same colloid after setting, on 
reheating fails to liquefy at this temperature — it usually first 
<: melts " at a higher one. In fact, it may be said quite generally 
that the curve showing the increase in viscosity of a lyophilic 
colloid with lowering of temperature is rarely identical with that 
portraying (he decrease in viscosity when the temperature is 
raised through the same range. If the fact is remembered that the 
absolute values of two mutually soluble substances are rarely the 
same and that the rates at which they go into solution in each 
other are usually different, many of these difficulties disappear. 
Fig. 3 shows diagrammatically, not only what happens when the 
temperature of a solution of soap in water is lowered, but in the 
lower half of the pictures the effects of warming a gel. Increasing 
the temperature of the original solvated-soap shown in region Z 
increases the solubility of the soap in the water, and so the colloid 
dispersion Y results, consisting of soap-water in solvated-soap. 
Further increase in temperature yields the regions X and W, but, 
because of the persistence of the solvated-soap as the external 
phase, all these regions continue to show a rigidity or viscosity 



ABSORPTION, SECRETION— CELLS AND TISSUES 



59 



higher than that of systems of the same quantitative composition 
produced by a lowering of temperature from a higher level. The 
gel first shows signs of liquefaction when the soap-water particles 
begin to touch and thus form the external phase, as in the regions 
V and U. It is for these reasons that the region of greatest ambi- 
guity and of greatest hysteresis is found in the broken middle portions 
of the diagrams (D, E, F, and W, V, U). Just as long periods of 
time are required to make solution phenomena attain their end 
values, just so must mutually soluble systems subjected to changes 
in their environment be expected to come only slowly into a state 
of final equilibrium. 

In addition to this closer definition of hysteresis it is possible 
also to define more accurately gelation capacity and solvation or 
hydration capacity of a colloid. The latter measures the solubility 
of the solvent in the colloid material and is synonymous with 
swelling capacity. Gelation, however, includes not only this 
value but more — namely, everything embraced within the region 
of the emulsification of a " solution" of the colloid material in 
the solvent within the solvated colloid as an external "dry " 
phase. It embraces everything in Fig. 3 up to and including the 
zone V. 

Just above this region it is apparent that the more solid phase 
may no longer be adequate to enclose all the " solution " of colloid 
in solvent. When this upper region is reached the colloid system 
tends to "sweat " — or to use the term of Thomas Graham the gel 
shows syneresis. We may still have before us a gel, but it is now 
no longer "dry." 

To go sufficiently above the region U is to be in the regions E 
and D. We now no longer say that there is syneresis or that this 
has become excessive, but we say that the gel has gone into or 
persists in the sol state. 

It is of importance now to point out that in the discussion of 
Fig. 3 we have referred oftenest to Diagram A, in which it is 
assumed that the material (like soap) which falls out with a lower- 
ing of temperature is liquid in character. This, of course, it need 
not be. It may be solid. The matter is of importance in deter- 
mining the physical properties of the systems which are ultimately 
obtained. When sodium oleate, for example, falls out in water 
at ordinary temperatures, it does so in liquid form, but when 
sodium stearate is the soap in the system, it comes out in crystal- 



60 



(EDEMA AND NEPHRITIS 



line form, yielding a system like Diagram B). From both are 
derived hydrated or solvated systems, but it is obvious that 
crystals cannot be packed as uniformly or as compactly as 
can droplets. If the ultimate system consists of a solid mixed 
with liquid, it will approximate in physical characteristics such 
a mixture as that of sand with water, but, if it consists of a 
liquid mixed with liquid, its properties will more nearly ap- 
proximate an emulsion, as when a liquid oil is mixed with a 
liquid protein to form a mayonnaise. Systems of the former 
type will, for example, be more brittle, show more sudden 
transitions in physical properties, permit of a more rapid separa- 
tion of the one phase from the other and will sweat more easily 
and over longer ranges (show syneresis) than will the second 
group. 1 

As a final word it needs to be emphasized that the concept 
of the lyophilic colloid as here outlined sets no limitations upon 
the nature of the materials that may make up such a system and 
makes no specification as to the nature of the forces which guarantee 
the stability of the colloid system. They are, in general, any or 
all the forces which appear in or are operative in solutions of 
the most varied kinds. This is emphasized because there has 
been much written, for example, regarding the all-important 
effects of such single elements as the electrical charges in 
determining the stability of colloids in general and of the 
lyophilic colloids in particular. We do not wish to deny the 
importance of this factor in some colloid systems or under certain 
conditions, but it is too narrow a view to take of what con- 
stitutes the lyophilic colloids in general. While the play of 
electrical forces may be apparent in systems composed of soaps 
and water or proteins and water, lyophilic colloid systems may 
be built up in which the electric factors are either negligible or 
absent. It is somewhat difficult, to say the least, to conjure up 
orthodox electrical notions in such beautiful gels as may be 
made from nothing but soaps with anhydrous alcohol, toluene, 
benzene, chloroform or ether. 

1 It is in this larger classification of the coDoid systems (after their 
definition as lyophobic or lyophilic systems in the terms given above) that 
the concepts of Wolfgang Ostwald covering the importance of the 
physical state (gaseous, liquid and solid) of the phases subdivided into each 
are of such fundamental significance. 



ABSORPTION, SECRETION— CELLS AND TISSUES 61 



With these remarks in mind on the nature of the lyophilic or 
hydrophilic colloids in general we may now turn to a more specific 
study of such as appear in living cells. When it is recalled that 
the hydrophilic colloids which have thus far been accorded most 
study — gelatin, glue, albumin, dextrin, starch, vegetable fibers, 
gums — are all derived from biological sources, their probable 
importance in the living animal or plant must at once be sus- 
pected. Not only is the chief mass of the living organism built up 
of colloid material, but most of it belongs in the hydrophilic 
group. We will not be surprised, in consequence, to find 
that those physico-chemical characteristics which made for 
the division of all colloids into two great classes will show 
themselves of importance in determining the behavior of the 
tissues toward water. 

It will give us a better conception of just what this absorption 
of water by colloids represents, and how it is influenced through 
various external conditions, if we study the swelling of some 
proteins. 

2. Observations on the Swelling of Fibrin 

In these experiments ordinary blood fibrin was used, which after 
having been thoroughly washed to free it from adhering salts 
was dried at a low temperature and pulverized in a mortar. 
When weighed amounts of such powdered fibrin (0.25 gram) 
are introduced into definite volumes (25 cc.) of various solutions 
contained in test-tubes of the same diameter (1.7 cm.) the fibrin 
swells to very different heights. From the results of many series 
of experiments, the following facts which are of importance in 
our discussion have been determined. 1 

(a) Fibrin swells more in the solution of any acid than it 
does in distilled water. Table I illustrates this fact. While 
the exact order changes somewhat at different concentrations 
the table also serves to indicate that when equinormal acids 
are compared, they are found to be very unequally effective 
in producing the swelling. A hasty glance suffices to show 
that we are not dealing with the simple effects of hydrogen 

1 See Martin H. Fischer and Gertrude Moore: Am. Jour. Physiology, 
20, 313 (1907); Kolloid-Zeitschr., 5, 197 (1909); Martin H. Fischer, 
Pfliiger's Archiv., 125, 99 (1908). 



62 



(EDEMA AND NEPHRITIS 



ions determined by the relative degrees of dissociation of the 
various acids, for while a " strong " acid (hydrochloric) stands 
at the top of the list, another (sulphuric) stands at the very 
bottom, while a series of "weak" organic acids are found 
between. 



TABLE I 
Fibrin — Acid 



All acids n/10 


Height of fibrin 
column in mm. j 
after 24 hours. 


All acids n/10 


Height of fibrin 
column in mm. 
after 24 hours. 


Water 


6 
28 
27 
27 
24 

1 


Oxalic 


24 
20 
10 
9 

8 


Phosphoric 

Lactic 


Citric 




Sulphuric 



The amount that fibrin swells in any acid solution is dependent 
upon the concentration of the acid. Within certain limits fibrin 
swells the more the higher the concentration of the acid. In 
the case of the " strong " acids, however, a maximum is attained, 
above which a further increase in the concentration of the acid 
does not lead to a greater, but to a diminished absorption of water. 
The swelling of fibrin in acid solutions of progressively higher 
concentrations may therefore be represented graphically by a 
curve which rises at first, attains a maximum and then falls 
again. These facts are brought out in Table II. In the case 
of acetic acid it will be noted that the highest concentration 
of acid used in the table induces the greatest amount of swelling. 
At concentrations above n/10, 1 obtained a height up to 41 mm. 
with this acid. As yet I have not, however, been able to deter- 
mine if with such a " weak " acid a point is finally reached be- 
yond which, as with the " strong " acids, a further increase in 
concentration brings about a diminished absorption. No greater 
swelling of fibrin than that noted in the table can be obtained 
by using concentrations of sulphuric acid above those given 
in Table II. 

(b) Fibrin swells more in the solution of any alkali than 
in pure water, but the amount of .this swelling is greater in 



ABSORPTION, SECRETION— CELLS AND TISSUES 

TABLE II 
Fibrin — Acid 



63 



Concentration of acid. 



1 

2 
3 
4 
5 
6 
7 
8 
9 
10 

un 

15 
17 H 
20 
25 
25 



n/10 acid +24 < 
+23 
+22 
+21 
+20 
+ 19 
+18 
+ 17 
+16 
+ 15 
+12V 2 
+10 
+ 7V 2 
+ 5 



H 2 0. 



water (control) 



Height of fibrin column in mm. after 
24 hours in 



Hydro- 
chloric 
acid. 



Nitric 
acid. 



Acetic 
acid. 



Sul- 
phuric 
acid. 



21 



13.5 

26. 

29. 

37.5 

35. 

30. 

30. 

25. 

23. 

21.5 

18.5 

17. 

14.5 

14. 

11.5 



8.5 
10. 
10.5 
11. 
12. 
12. 
13. 
13. 
14. 
14.5 
15. 
16. 
17. 
18. 
18.5 



8. 

9. 

9.5 
10. 
10. 
11. 
11. 
10. 
10. 
10. 
10. 



8.5 
8.5 



some alkalies than in others. This statement is the analog 
of the corresponding one for acids. When equinormal solu- 
tions are compared fibrin swells more in potassium hydroxid 
than in sodium hydroxid, and more in either of these than 
in calcium hydroxid or ammonium hydroxid in the order 
named. 

The first three of these have in such dilute solutions about 
the same degree of dissociation. Clearly, the amount of swelling 
is not simply a function of the hydroxyl ions. As in the case of 
acids, the amount of swelling is here also dependent upon the 
concentration of the alkali. For the " strong " alkalies there 
is within certain limits an increase in the amount of swelling 
with every increase in the concentration of the alkali, but, after 
a certain point is exceeded a further increase in concentration 
is followed by a diminution in the height of the fibrin column. 
Tables III and IV illustrate these facts. 

If the amounts that fibrin will swell in acid and alkali solu- 
tions having the same H or OH concentration are compared, 
it is found that fibrin swells less in the solution of an acid than 
in an equally concentrated solution of an alkali. While, for 



64 



(EDEMA AND NEPHRITIS 



example, in n/50 KOH or NaOH, the fibrin column may be 
found to measure 83 and 77 mm. respectively, in n/50 HC1 or 
HNO3 it measures only 48 and 35 mm. 



TABLE III 
Fibrin — Alkali 



Concentration of alkali. 



cc. n/10 alkali +23 cc. H 2 0. 

+21 " . 
+19 V . 
+15 " . 
+10 '« . 



25 cc. water (control) . 



Height of fibrin column in 
mm. after 24 hours. 



KOH 


NaOH 


NH4OH 


23 


22 


10 


64 


58 


10.5 


83 


77 


11 


80 


75 


11 


72 


62 


12 


58 


57 


13 


8 


8 


8 



TABLE IV 
Fibrin — Alkali 





Height of fibrin column in 




mm. after 24 hours. 


Concentration of alkali. 








NaOH 


Ca(0H) 2 1 




12.5 


13 


2 " " +23 " 


23 


15 


3 " " +22 " 


40 


17 




66 


18 




75 


18 


6 " " +19 " :. 


75 


15 




75 


16 




74 


15 




73 




10 ** ** +15 ** . 


68 




12J4 " " +123^ " 


64 






61 




1714 " " + 7V 2 " 


57 




20 *' " +5 ** ; 


57 






53 






8 





1 Actually these solutions were prepared by diluting n/30 Ca(OH) 2 . 



(c) We come now to the interesting fact that the addition of 
any salt to the solution of an acid or an alkali decreases the 
amount that fibrin will swell in that solution. The only excep- 
tions to this rule are formed by the salts which react with the 
acids. If barium chlorid, for example, is added to a sulphuric 
acid solution, the amount of swelling is not decreased, but in- 



ABSORPTION, SECRETION— CELLS AND TISSUES 65 



creased. This is because insoluble barium sulphate is produced 
and thrown down, while hydrochloric acid is formed in which 
fibrin swells more than in an equally concentrated sulphuric 
acid solution. 

The higher the concentration of the added salt, the less does 
the fibrin swell, and if enough is added the effect of the acid or 
alkali may be suppressed almost entirely. These facts are 
illustrated in Tables V and VI and in Fig. 4. The tube on the 




Figure 4. 



extreme right contains the unit weight of powdered fibrin in 
water. The tube marked HC1 contains the same weight of 
fibrin in n/40 acid. The remaining tubes from right to left 
contain the same amounts of acid and of fibrin, but progressively 
greater concentrations of sodium nitrate (from m/40 to m/5 in 
the finished solution). 

(d) If the effect of equimolar 1 salt solutions is compared, 

1 To make proper comparisons between the physiological or pharmaco- 
logical actions of different chemical compounds, ordinary equivalents by 
weight (as in percentage solutions) cannot be used. We must compare 



66 



(EDEMA AND -NEPHRITIS 



TABLE V 
Fibrin — Acid + Salt 







Height of fibrin column in mm. 








after 24 hours. 






Concentration of solution. 














KC1 


MgCl 2 


(NH 4 ) 2 S0 4 


KI 


15 




9 


6 


5 


5 


15 


+ 15 " m/4 " 


10 


8 


6 


5 


15 


+15 " m/8 " 


13 


9 


7 


6 


15 


+ 15 " m/16 " 


14 


10 


10 (?) 


10(?) 


15 


+15 " m/32 *' 


15 


10 


9 


9 


15 













TABLE VI 
Fibrin — Alkali+Salt 



Concentration of solution. 



Height of fibrin 
column in mm. 
after 24 hours. 



n/10 NaOH+12 
+ 10 

+ 8 
+ 6 
+ 4 
+ 3 
+ 2 
+ 1 



m/1 NaCl+ 8 cc. H 2 0. 

+10 " . 

+12 " . 

+14 " . 

+16 " . 

+17 " . 

+18 " . 

+19 " . 



+20 cc. water. 



25 cc. water (control) 



19 
21 
21 
24 
28 
30 
32 
43 
74 
8 



amounts that are equivalent from certain chemical or physico-chemical 
points of view. For many purposes molar (pram-molecular or molecular) 
solutions serve very well. A molar solution (m/1) is made by dissolving the 
molecular weight of the substance (including its water of crystallization, if 
it has any) expressed in grams in enough water to make a liter. If only 
one-half the gram-molecular weight is dissolved in enough water to make a 
liter, we have a one-half molar solution (m/2), etc. Solutions which con- 
tain the same number or fractions of a gram-molecule in the unit volume are 
equimolar. 

In the case of acids and alkalies it is usually best to employ normal 
solutions. A normal solution (n/1) is a molar one provided the dissolved 
substance is monobasic. In other words, its power to displace hydrogen is 
taken into consideration. A normal solution of a dibasic compound has 
half the concentration of a molar solution of the same compound; a normal 
solution of a tribasic compound but one- third, etc. Equinormal solutions 
of different acids or alkalies therefore all contain the same amount of replace- 
able hydrogen or hydroxyl. 

The " physiological " or " normal " salt solutions of our laboratories 
and hospitals have absolutely nothing to do with the normal solutions of 
the chemists which we are discussing. The terms are meaningless, and 
should disappear. We should speak of 0.85 per cent or 0.9 per cent sodium 
chlorid solutions if that is what we mean by these terms. 



ABSORPTION, SECRETION— CELLS AND TISSUES 67 



they are found to affect the swelling of fibrin in solutions of acids 
or alkalies to very unequal degree. This is readily apparent 
from Fig. 5. where the effect of adding molecularly equivalent 
amounts of various sodium salts to a hydrochloric acid solution 
is portrayed. The tube on the extreme left contains pure water 
only. The next contains pure hydrochloric acid (n/40). From 
left to right the succeeding tubes contain the same amount of 
hydrochloric acid plus various sodium salts (n/40 HC1 in m/40 




salt solution). The salts added from left to right are respectively 
the chlorid, bromid, nitrate, iodid, acetate, tartrate (of sodium 
and potassium), sulphate, phosphate and citrate of sodium. 

The tube on the extreme left in Fig. 6 contains a pure n/40 
solution of sodium hydroxid. The remaining tubes show the 
effect of adding molecularly equivalent (m/40) amounts of various 
sodium salts to the pure sodium hydroxid solution. From left 
to right the salts added are the bromid, nitrate, acetate, tartrate, 
sulphate, citrate and phosphate of sodium. 



68 



(EDEMA AND NEPHRITIS 




ABSORPTION, SECRETION— CELLS AND TISSUES 69 



From the study of many series of salts it has been found that 
the effect of any salt is made up of the sum of the effects of its 
constituent radicals. In any series of salts having a common 
base the order in which the acid radicals are effective is always 
found to be the same, and when series having a common acid 
are compared, the order in which the basic radicals are effective 
is always the same. From such experiments the two following 
lists have been constructed. The radical least effective in bring- 
ing about a diminution in the amount that fibrin will swell in 
the solution of any acid or alkali is in each case placed first: 



Acid radicals. 


Basic radicals. 


Chlorid 


Potassium 


Bromid * 


Sodium 


Nitrate 


Ammonium (?) 


Sulphocyanate 


Magnesium 


Iodid 


Calcium 


Acetate 


Barium 


Sulphate 


Strontium 


Phosphate 


Copper (ic) 


Tartrate 




Citrate 


Iron (ic) 



The table for the acid radicals is more accurate than the table 
for the basic radicals. This is because the amount of difference 
in swelling produced by the end members of each of the two 
series is decidedly greater in the case of the acid radicals than 
in the case of the basic radicals. The general grouping of the 
basic radicals is, however, entirely trustworthy. While the differ- 
ence between the amount of swelling in an acid solution con- 
taining a magnesium salt may not differ cfecidedly from a similar 
solution made up with a calcium or barium salt, there is never 
any question about the difference between the action of any of 
these three and that of a radical found in the list either above 
or below them. 

(e) Non-electrolytes do not share with electrolytes their 
marked power of reducing through their presence the amount 
that fibrin will swell in the solution of any alkali or acid. In 
concentrations that are from an osmotic standpoint comparable 
to those used above in the case of salts, the non-electrolytes are 
almost without effect, as shown in Tables VII and VIII: 



70 (EDEMA AND NEPHRITIS 

TABLE VII 



Fibrin — A cid+ Non-electrolytes 







Height of fibrin 


Concentration of the solution. 


column in mm. 






after 24 hours. 


10 cc. n/5 HC1+10 cc. 


H 2 


28 


10 " " +10 " 




30 


10 " " +10 " 




28 


10 " " +10 ' 




27.5 


10 " " +10 " 




27 


20 op wnt.pr fnontrnn . . . 




8 





TABLE VIII 



Fibrin — A Ikali + Non-electrolytes 







Height of fibrin 


Concentration of the solution. 


column in mm. 






after 24 hours 


10 cc. n/10 KOH + 4 cc. 




76 


10 " " +4 " 


" methyl alcohol +11 " 


77 


10 " " + 4 " 




72 


10 " " +4 " 




83 


10 " " + 4 " 


" saccharose +11 " 


75 


10 " " +15 " 


H 2 


77 


10 " " +10 " 




73 


10 " " +10 " 




73 


10 " " +10 " 




64 


10 " " +10 " 




80 


10 " " +15 " 




75 


10 " " +15 " 


H 2 


78 






8 





Not until employed in rather concentrated solutions do 
glycerin, saccharose, dextrose, ethyl alcohol and methyl alcohol 
change in any marked way the height to which a fibrin column 
will swell in various concentrations of acid or alkali. 

(/) For purposes of biological application a series of tables 
are inserted here which show the effect of different non-electrolytes 
upon the absorption of water in a neutral medium. Saccharose, 
dextrose, levulose, methyl alcohol, propyl alcohol and acetone 
will inhibit more or less markedly the amount of water that fibrin 
will absorb. 1 Of these, the behavior of saccharose, dextrose 
and levulose deserve special mention. While all three dehydrate 
fibrin in increasing amount with increase in concentration, at 
the same concentration saccharose is the most powerful in 



1 Martin H. Fischer and Anne Sykes: Kolloid-Zeitschr., 14, 215 (1914). 



ABSORPTION, SECRETION— CELLS AND TISSUES 71 



this regard. Tables IX, X and XI suffice to illustrate this fact, 
which will be more emphatically brought out in discussing the 



oKorvm+inn f\f tutq tor rvir frol cilin 
diUbLupUlUll Ul WctUcl Uy geld till. 




TABLE IX 




TTt'R'rtm SinfrhnT/ttP 




Concentration of solution. 


Height of fibrin 




column in mm. 




23 




22 


2 " " +38 " 


22 


3 " " +37 " 


21 


5 " " +35 " 


21 




01 

Z 1 


10 " " +30 " 


20 


20 " " +20 " 


18 


TABLE X 




r ibrin — Dextrose 




Concentration of solution. 


Height of fibrin 




column in mm. 




21 




21 


2 " " +38 " 


20 




20 


5 " " +35 " 


19 


" " +32^ " 


19 


10 " " +30 " 


18 




17 


40 *' " 


15 





TABLE XI 



Fibrin — Levulose 



Concentration of solution. 


Height of fibrin 
column in mm. 




21 




20.5 


2 " *' +38 " 


20.5 




20.5 


5 '* " +35 *.' 


20 


7K *' " +32^ " 


20 


10 " " +30 " 


20 




19 



(g) The taking up and giving off (absorption and secretion) 
of water by fibrin represents in high degree a reversible process. 



72 



(EDEMA AND NEPHRITIS 



If for a hydrochloric acid solution in which fibrin has attained 
its maximal swelling, an equally concentrated sulphuric acid 
solution is substituted, the fibrin column shrinks. The same 
occurs if a potassium hydroxid solution is replaced by an equally 
concentrated calcium or ammonium hydroxid solution. When 
equilibrium is finally established the height of the fibrin column 
in each of these solutions is approximately equal to that which 
would have been attained had the fibrin been placed directly 
in these solutions. In the same way fibrin which has attained 
its maximal swelling in an acid solution will shrink rapidly if 
for the pure acid there is substituted one of equal concentration 
containing a salt. Similarly, if water replaces the solution of 
an acid or an alkali, the fibrin will either shrink or swell more, 
depending upon whether the addition of the water makes the 
concentration of the alkali move toward or away from that which 
is optimal for the swelling of fibrin. (See paragraph b of this 
section.) 

The reverse of all these experiments can also be accomplished, 
although not with the same ease. If, for example, hydrochloric 
acid is substituted for sulphuric, or potassium hydroxid for the 
calcium compound, an increase in the amount of swelling is noted, 
but the column does not rise as high as it would have done if 
placed directly in these solutions. Similarly, fibrin which has 
once been in an acid or an alkali solution containing a salt, when 
placed in pure solutions of acid or alkali does not swell to the 
amount which it would have done if it had been put in these 
solutions from the first. All this would seem to indicate that 
fibrin suffers more or less permanently from every external con- 
dition to which it has been subjected. To explain this phe- 
nomenon, which is of great importance from both the theoretical 
and the practical aspects of biology and medicine, we can advan- 
tageously call to mind the well-known property of colloids of 
attaching to themselves, and holding fast the various substances 
with which they come in contact. 1 

(h) For reasons associated with our analysis of the problem 
of oedema we are particularly interested in substances which are 
capable of increasing the amount of water held by such a colloid 
as fibrin. Among other substances besides acids and alkalies 

1 See page 210, where is discussed the taking up of dissolved substances 
and the phenomena of adsorption. 



ABSOKPTION, SECRETION— CELLS AND TISSUES 73 



capable of thus increasing the hydration capacity may be men- 
tioned urea and pyridin. 1 The hydrating effect of urea is 
already indicated in Tables VII and VIII, but is more clearly 
evidenced in Table XII. The hydrating effect of pyridin is 
illustrated in Table XIII. The calibrated test-tubes used in 
these particular experiments were 22 mm. in diameter, 40 cc. of 
solution were prepared and a gram of dry fibrin was employed. 

TABLE XII 



Fibrin — Urea 







Height of fibrin 




Concentration of solution. 


column in mm. 






after 24 hours. 


40 cc. 




17 


1 cc. 


5/m urea +39 cc. H 2 


18 


2 " 


+38 " 


19 


3 '* 


+37 " 


19 


5 " 


+35 " 


19 


m " 


" +32^ '« 


20 


10 " 


+30 " 


22 


20 " 


+20 " .' 


25 


40 " 




39 






TABLE XIII 






Fibrin — Pyridin 








Height of fibrin 




Concentration of solution. 


column in mm. 






after 24 hours. 


40 cc. water (controls „ = 


20 


1 cc. 


10/m pyridin +39 cc. H 2 


22 


2 " 


+38 " 


23 


3 " 




24 


5 " 


Sj&V* +35 " 1 '. 


25 


7V 2 " 


+32^ " 


26 


10 " 




28 





(i) An interesting and biologically important difference exists 
between the increased hydration brought about by substances 
of the type of urea or pyridin and that brought about through 
acids. That produced through acids is readily reducible through 
all salts. Salts do not reduce the increased hydration brought 
about either through urea or pyridin, as shown by Tables XIV 

1 See Martin H. Fischer and Anne Sykes: Science, 38, 486 (1913). 
Some of the amins seem also to belong in this group, but they are so pro- 
nouncedly alkaline in watery solution that a large part of their hydrating 
effect seems to be dependent upon this alone. 



74 



(EDEMA AND NEPHRITIS 



and XV. The slight power of some salts to increase the hydra- 
tion of (neutral) fibrin is merely found added to that produced 
by urea or pyridin alone. On the other hand, various non- 
electrolytes, such as the sugars, which affect the swelling of 
fibrin in acid solutions but little, produce a marked shrinkage when 
the increased hydration has been produced by urea or pyridin. 
This is shown in Tables XVI and XVII. 

TABLE XIV 
Fibrin — Urea + NaCl 



Concentration of solution. 



Height of fibrin 
column in mm. 
after 24 hours. 



40 cc. water (control) . . . 

20 cc. 5/m urea +20 cc. 

20 ", 'V +20 cc. 

20 " " +15 " 

20 " " +10 " 

20 " " + 5 " 

20 " " + 2V 2 " 

20 " + 1 " 



H 2 

m/1 NaCl, 



+ 5 cc. H 2 0. 
+ 10 V . 
+15 *' . 
+17V 2 " . 
+19 " . 



18 

30 
36 
35 
35 
33 
33 
32 



TABLE XV 
Fibrin — Pyridin + NaCl 



Concentration of solution. 



Height of fibrin 
column in mm. 
after 24 hours. 



40 cc. water (control) 

10 cc. 10/m pyridin +30 cc. H 2 

10 " " +20 cc. m/1 NaCl +10 cc. H 2 

10 " " +10 " " +20 

10 " *' +5 " " +25 " 

10 " " + 2V 2 " " +27H " 



TABLE XVI 
Fibrin — Urea + Saccharose 



Concentration of solution. 



cc. water (control) . 
cc. 5/m urea +20 
+20 
+15 
+ 10 
+ 5 
+ 3 
+ 2 
+ 1 



H 2 

2/m saccharose. 



+ 5 cc. 
+10 ' 
+ 15 ' 
+17 ' 
+ 18 ' 
+ 19 ' 



H 2 0. 



Height of fibrin 
column in mm. 
after 24 hours. 



19 
29 
20 
20 
20 
20 
20 
20 
21 



ABSORPTION, SECRETION— CELLS AND TISSUES 

TABLE XVII 
Fibrin — Pyridin + Saccharose 



75 



Concentration of solution. 



40 cc. water (control) 

10 cc. 10/m pyridin +30 cc. H 2 

10 " " +20 cc. 2/m saccharose +10 cc. H2O 

10 " " +10 " " +20 " 

10 ~" " + 5 «' ** +25 " 

10 " " + 2Y % " " +27V 2 " 



Height of fibrin 
column in mm. 
after 24 hours. 

• 20 
29 
25 
26 
27 
28 



3. Observations on the Swelling of Gelatin 

We have now to consider whether the behavior of fibrin in 
various solutions is characteristic of this substance alone, or 
whether we have simply discussed as applicable to one colloid, 
properties that are really common to many. A partial answer 
to this question can be found in the careful studies available 
on the swelling of gelatin and other proteins. The observations of 
Fkanz Hofmeister, 1 Wolfgang Pauli, 2 K. Spiro 3 and Wolf- 
gang Ostwald 4 show gelatin to behave in many ways simi- 
larly to fibrin. We will review some of these in so far as they 
are of interest to us in the study of our problem. At the same 
time experiments of our own will be introduced which not only 
serve to corroborate the various findings already made on the 
swelling of gelatin but augment these, particularly in the following 
directions. They show (1) the unequal effect of different equi- 
normal and equally dissociated acids and alkalies upon the swell- 
ing; (2) the antagonism between neutral salts and acids or alkalies 
upon it; (3) the comparative lack of antagonism between non- 
electrolytes and acids or alkalies upon the absorption of water 
by this substance; (4) the reversibility of the absorption of water 
by this substance. They discuss also (5) other substances besides 
acids which are capable of increasing the hydration capacity of 
gelatin and show (6) how such hydration is not reduced through 
salts, but readily through various non-electrolytes which are 

1 Franz Hofmeister: Archiv. f. exp. Path. u. Pharm., 27, 395 (1890). 

2 Wolfgang Pauli: Pfliiger's Archiv., 67, 219 (1897); ibid., 71, 1 (1898). 
3 K. Spiro: Hofmeister's Beitrage zur chem. Physiologie, 5, 276 (1904). 
4 Wolfgang Ostwald: Pfliiger's Arch., 108, 563 (1905). 



76 



(EDEMA AND NEPHRITIS 



comparatively ineffective in reducing the swelling induced through 
acid. 

Our experimental methods differed in no material way from 
those usually followed by workers in this field. Ostwald's 
scheme was adopted. One part of the best commercial gelatin 
was dissolved at a low temperature (45° C.) in four parts of water 
and poured into shallow pans. After having hardened in an ice- 
chest the gelatin was cut with the aid of a sharp knife and a ruler 
into squares of uniform size. These squares were allowed to 
dry upon glass plates at room temperature. The drying process 
took from six to ten days, and was not sufficiently rapid to distort 
the squares. When completely dry the squares measured about 
18X18X2.5 mm. and weighed approximately 0.8 gram. As a 
uniform material is necessary to obtain comparable results, it 
is well to mention that all the gelatin discs used in any extended 
series of experiments were always prepared at the same time. 
The course of the absorption of water by the discs was followed 
by immersing the weighed gelatin discs in solutions of various 
kinds and weighing them at intervals. 

In order to facilitate comparison with the results obtained on 
fibrin the paragraphs on gelatin are lettered in the same way 
as the paragraphs on fibrin. It will be seen that gelatin is a 
colloid which behaves in many ways like fibrin. Important 
differences, however, exist between the two, which we shall later 
find to be not without biological interest. 

(a) Gelatin swells more in the solution of any acid than it 
does in water. This fact is readily apparent even to the naked 
eye. If two gelatin discs are dropped at the same time, the one 
into water, the ether into n/20 hydrochloric acid, the in- 
equality in the amount of swelling is plainly to be seen at the 
end of six hours, and at the end of twenty-four or forty-eight 
it is very marked. While at this time the gelatin disc in the 
water still has a slightly brownish-yellow and opaque appearance, 
that in the acid is hyalin and perfectly clear, so clear, in fact, that 
it can scarcely be seen at the bottom of the dish. Spiro, who 
first discovered this difference in the amount that gelatin will 
swell in water and in acids, found that while a gelatin plate gained 
1.97 times its weight in water, it gained 3.49 times its weight in 
n/500 hydrochloric acid, and 5.45 times its weight in n/200 
acid. Ostwald came to the same conclusion from comparison 



ABSORPTION, SECRETION— CELLS AND TISSUES 77 



of his results on the swelling of gelatin plates in acids of various 
kinds with the absorption curves of gelatin in water, as given 

by HOFMEISTER. 

While the gelatin swells more in the solution of any acid than 
in water, the acids are by no means equally potent in this regard 
when equinormal solutions are compared. Most authors are 
inclined to the belief that the swelling induced in gelatin discs 
is exclusively a function of the hydrogen ion concentration. 
It seems to me that this is only in part responsible for the 
observed effects. I have taken the liberty of constructing 
from Ostwald's 1 tables the curves contained in Figs. 7 and 8. 





hnos/ 


HC 2 H 3 02^ 


^^H^SOt 




















GELATIN 










acids 





} 8 16 24 32 40 48 56 64 72 

Hours 



Figure 7. 



"The hours that the gelatin discs were in the acid solutions are 
plotted on the horizontal, the amount of water absorbed, expressed 
in units of the original weight of the disc, is shown on the vertical. 
We have no difficulty in recognizing in Fig. 7 the order: 

Nitric, Acetic, Sulphuric, Boric. 

The position of the " weak " acetic acid between the " strong " 
nitric and sulphuric acids (which two are about equally dis- 
sociated, and yield a higher concentration of hydrogen ions than 
the equinormal acetic acid) is by itself an argument against the 
explanation which considers only the concentration of the hydrogen 

Wolfgang Ostwald: Pfluger's Arch., 108, 577 and 578 (1905). 



78 



(EDEMA AND NEPHRITIS 



ions. A look at Fig. 8 brings with it similar conclusions. Except 
in the first hours of the experiment, we again find the order: 

Hydrochloric, Nitric, Acetic, Sulphuric, Boric. 

This order in which the different acids make gelatin swell 
is identical with that in which they make fibrin swell. 

The amount that gelatin swells in any acid solution is de- 
pendent in a complex way upon the concentration of the acid. 
This is shown in Fig. 9, which has been copied from Ostw t ald's 



24- 

22 
20 






IS 






16 




HN0 3 


14 






12 






10 


y / h 2 so. 




8 
6 


/y/ ^^^to 2 h 3 o 2 




4 


■ J/. /^^^^^* S3B03 


GELATIN 

it acids 


2 














4 8 12 16 20 32 44 56 68 

Hours 

Figure 8. 



article. The curve marked HC1 indicates the amount of water 
absorbed by gelatin plates after twentj^-four hours residence in 
hydrochloric acid solutions of various concentrations. With the 
exception of the initial fall in the curve (which simply indicates 
that in hydrochloric acid solutions of certain concentrations a 
gelatin disc may absorb even less than in pure water) we notice 
a rapid rise in the curve indicative of an increase in the amount 
of swelling with every increase in the concentration of the acid. 
An optimal point is reached when the concentration of (approxi- 
mately) n/38 hydrochloric acid is attained, beyond which a 



ABSORPTION, SECRETION— CELLS AND TISSUES 79 



further increase in the concentration of the acid is not followed 
by a greater absorption of water, but by a less. 

An analogous relationship between concentration of acid and 
amount of swelling exists in the case of fibrin. 




(b) Gelatin swells more in the solution of any alkali than in 
water. Macroscopic examination alone evidences this fact. 
Spiro, 1 who first noted it, found that while a gelatin disc kept 
in pure water gained only 3.02 times its weight of water, one kept 

1 K. Spiro: Hofmeister's Beitrage z. chem. Physiologie, 5, 277 (1904). 



80 



(EDEMA AND NEPHRITIS 



in n/100 sodium hydroxid solution gained 5.08 times its weight, 
one in n/50 solution, 11.82 times its weight, and one in n/10 
solution, 12.61 times its weight of water. 

When the effect of equinormal solutions of different alkalies 
is compared, it is found that a gelatin disc swells more in some 
alkalies than in others. This statement, which has its analogue 
in -the acids, is illustrated in Fig. 10. The hydroxids show the 
following grouping, in which that which allows of the greatest 
swelling is placed first: 

Potassium, Sodium, Calcium, Ammonium. 

At the concentrations employed, the electrolytic dissociation 
of the first three is about the same. The conclusion, therefore, 
seems justified that the swelling of gelatin in various alkalies 









KOH^^^ 




^J^NaOH 




Ca(OH)^^"^ 




^^^^^I^HiOH 




GELATIN 




alkalies 



8 16 24 32 40 48 56 64 

Hours 

Figure 10. 



is not solely determined by the concentration of the hydroxyl 
ions, but perhaps by these minus the effect of the kation, calcium 
being more active in bringing about a reduction in swelling than 
sodium, and this more than potassium. Fig. 10 has been con- 
structed from the data contained in Table XVIII. As the 
increase in weight in these experiments on gelatin is very large, 
uselessly cumbersome figures have been avoided by expressing 
changes in weight in parts of the original weight of the (dry) 
gelatin. One part, therefore, corresponds to an increase in 
weight of 100 per cent. 



ABSOKPTION, SECKETION— CELLS AND TISSUES 81 



TABLE XVIII 
Gelatin — Alkali 



Dry weight of gela- 
tin disc. 


0.830 


0.830 


0.830 


0.822 


Solution. 


150 cc. n/30 
KOH. 


150 cc. n/30 
NaOH. 


150 cc. n/30 
Ca(OH) 2 . 


150 cc. n/30 
NH4OH. 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


10.05 
21.25 
34.25 
58.20 


5.5 
8.9 
12.8 
18.6 


5.3 
8.7 
12.5 
17.7 


3.4 
5.2 
7.4 
11.9 


3.4 
5.0 
6.8 
8.8 



As in the case of hydrochloric acid, we find with potassium 
hydroxid also that the amount of swelling is dependent in a com- 
plex way upon the concentration of the alkali. This is well shown 
in the curve marked KOH in Fig. 9, copied from Ostwald. . It 
indicates the amount of water absorbed by gelatin discs after 
twenty-four hours residence in various concentrations of potas- 
sium hydroxid. The initial rise in the curve indicates how with 
an increase in the concentration of the alkali there is an increase 
in the amount of swelling; but, as with the acid, an optimal point 
is soon reached beyond which a further increase in the concen- 
tration of the potassium hydroxid leads to a diminished absorption 
of water. 

If the amounts that gelatin will swell in equinormal solu- 
tions of acids and alkalies are compared, it is found that gelatin 
swells somewhat less in the solution of an alkali than in an equally 
concentrated acid. This fact, which is the reverse of that found 
for fibrin, is well illustrated in Fig. 9 and in the upper two curves 
of Fig. 8, copied from Ostwald's studies. It finds a ready expla- 
nation, it seems to me, in the experiments which follow. Com- 
mercial gelatin is distinctly acid. When placed in the solu- 
tion of an alkali, a salt is therefore formed, the presence of which, 
as the next paragraph shows, markedly decreases the amount 
that gelatin will swell in any acid or alkaline liquid. 

(c) The addition of. any salt to the solution of an acid or an 
alkali decreases the amount that a gelatin disc will swell in that 
solution. As the number of insoluble hydroxids is large, studies 
on the antagonism between acids or alkalies and salts were carried 
out chiefly with acid solutions. Fig. 11, as well as Figs. 12, 13, 14, 



82 



(EDEMA AND NEPHRITIS 



15, 16, 17 and 18, illustrates this point. In Fig. 11 is compared the 
swelling of a gelatin disc in a pure hydrochloric acid solution, 
with the swelling of gelatin discs placed in equally concentrated 
hydrochloric acid solutions to which have been added equimolar 
amounts of various ammonium salts. As clearly evident, the 
amount of swelling is in every instance much less in these solutions 



22 
20 








RELATIN 




18 


Ammcmi urn-Series 




16 






14 




/fi hci 


12 






10 




Chlorid ^-sass^ 






Bromid - 


8 




Nitrate^ 


6 






4 




Sulphate 






Acetate 


2 














Hours 
Figure 11. 

than in the pure hydrochloric acid. Fig. 11 has been constructed 
from the data contained in Table XIX. 



TABLE XIX 
Gelatin — A aid +Salt 



Dry weight of 
gelatin disc. 


0.802 


0.806 


0.813 


0.814 


0.817 


0.817 


Solution. 


50 cc. 
n/10 
HCl +50 
cc. H 2 0. 


50 cc. 
n/10 
HCl+50 
cc. m/2 
ammonium 
acetate. 


50 cc. 
n/10 
HCl+50 
cc. m/2 
ammonium 
bromid. 


50 cc. 
n/10 
HCl +50 
cc. m/2 
ammonium 
chlorid. 


50 cc. 
n/10 
HCl +50 
cc. m/2 
ammonium 
nitrate. 


50 cc. 
n/10 
HCl +50 
cc. m/2 
ammonium 
sulphate. 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


10.25 
21.25 
34.25 
58.20 


7.6 
11.4 
15.3 
21.0 


2.8 
3.9 
4.8 
5.8 


3.3 
5.0 
6.7 
9.5 


3.4 
5.2 
6.9 
9.3 


3.2 
4.9 
6.6 
9.5 


2.9 
4.2 
5.3 
6.9 



ABSORPTION, SECRETION— CELLS AND TISSUES 83 



The higher the concentration of the added salt, the less does 
the gelatin swell, and if enough is added the effect of the acid 
or alkali may be almost entirely suppressed. This fact is brought 




out in Figs. 12, 13, 14, 15, 16 and 17. In each of these figures the 
curve for the swelling of the gelatin disc is found to lie nearer the 
base line with every increase in the concentration of salt employed. 



84 



CEDEMA AND NEPHRITIS 



(cf) When the action of equimolar salt solutions on the swell- 
ing of gelatin discs in acid or alkaline solutions is compared, 
it is found that some salts depress the amount of swelling more 




than others. This is already apparent in Fig. 11, in which the 
sulphate and acetate of ammonium have brought about a dis- 
tinctly greater inhibition in swelling than the chlorid, bromid 



ABSORPTION, SECRETION— CELLS AND TISSUES 85 



and nitrate. The point is further illustrated by comparing with 
each other Figs. 12, 13, and 14; also Figs. 15, 16, and 17. The 
hydrochloric acid curves of Figs. 12, 13, and 14 are practically 




identical. In all the figures a diminution in the amount of swell- 
ing is apparent through the addition of the salts, and the more 
salt added, the greater is this diminution. When Fig. 12 is com- 



86 



(EDEMA AND NEPHRITIS 



pared with Fig. 13, it is readily apparent that at the same con- 
centration potassium citrate brings about a greater depression 

of swelling in an 
acid solution than 
potassium chlorid. 
When, now, we 
compare Fig. 14 
with Fig. 12 we note 
that potassium sul- 
phocyanate acts 
more powerfully 
than potassium 
chlorid. When we 
compare Fig. 13 
with Fig. 14 we find 
that the extremes 
of the potassium 
citrate series lie be- 
tween the extremes 
of the potassium 
sulphocyanate se- 
ries. We cannot, in 
consequence, give 
an exact table indi- 
cative of the order 
in which the vari- 
ous acid radicals of 
salts with a com- 
mon base are active 
in depressing the 
amount that gela- 
tin will swell in an 
acid solution with- 
out stating the ex- 
act concentrations 
used. 

Figs. 15, 16 and 
17 permit a comparison of various basic radicals. 

When Figs. 15 and 16 are compared, it is readily apparent 
that calcium chlorid is more effective in inhibiting the swelling 




ABSORPTION, SECRETION— CELLS AND TISSUES 87 



solution than in potassium chlorid. All 
(with the exception of the pure hydro- 



of gelatin in an acid 
the curves of Fig. 16 
chloric acid curve) 
lie distinctly below 
the corresponding 
curves in Fig. 15. 1 
If we make a little 
allowance for ex- 
perimental errors 
we are probably 
safe in saying that 
the curves for sodi- 
um chlorid in Fig. 
17 occupy a posi- 
tion between those 
given for potassium 
chlorid and calcium 
chlorid. As the acid 
radical is the same 
in these salts, the 
differences may be 
attributed to the 
effect of the basic 
radicals which as- 
sume the following 
familiar order in 
which that least 
effective in reduc- 
ing the swelling of 
gelatin is placed 
first. 

Potassium, Sodium, 
Calcium 

As the concen- 
trations of acids 
and salts employed 

1 That curve V in Fig. 16 lies above IV represents an experimental error. 
The dry gelatin disc used for curve V was not as heavy as that used for curve 
IV. Thin discs swell faster. 




88 



(EDEMA AND NEPHRITIS 



are the same in the experiments from which Figs. 12 and 15 (the 
two potassium chlorid series) have been constructed, the ques- 
tion arises why the 
curves in the latter 
lie lower than those 
in the former. The 
gelatin and all ex- 
ternal conditions 
were the same in 
these two sets of 
experiments except 
the temperature, 
and it is to the 
higher temperature 
prevailing when the 
experiments of Figs. 
12, 13 and 14 were 
carried out (Sep- 
tember 4 to 7,1908) 
than when those 
of Figs. 15, 16 and 
17 were made 
(November 11 to 
20, 1908), that I at- 
tribute the marked 
absolute differences 
in the amount of 
the swelling. 

A point that we 
will find of biologi- 
cal interest later is 
well brought out in 
Figs. 12 to 17. This 
is the amount of 
inhibition in the 
swelling with any 
unit increase in the 
concentration of the added salt. It is clearly evident that to double 
the concentration of the salt is not to double the diminution in swell- 
ing — in every case the diminution is less than might be expected. 




ABSORPTION, SECRETION— CELLS AND TISSUES 89 



In Fig. 18 is illustrated the effect of adding equimolar solutions 
of different sodium salts to a solution of sodium hydroxid. It 
is easily seen how much more powerfully the citrate, phosphate, 
tartrate and sulphate interfere with the swelling of the gelatin 
discs in this alkaline solution, than the various univalent acid 
radicals. The general grouping of the salts as to the way in which 




4 8 12 16 20 24 

Hours 

Figure 18. 

they affect the swelling of gelatin in solutions of acids and alkalies 
is therefore the same as that discovered in our study of the swelling 
of fibrin. 

Tables XX, XXI, XXII, XXIII, XXIV, XXV and 
XXVI contain the experimental data from which have been 
constructed, respectively, Figs, 12, 13, 14, 15, 16, 17 and 18. 



90 



(EDEMA AND NEPHRITIS 



TABLE XX 



Gelatin — Acid -\-Salt 



Dry wt. of 
gelatin disc. 


n son 


n Rf»9 
u . ou^ 


0.803 


0.809 


0.810 


0.813 


Solution. 


50 cc. 
n/10 
HCl+40 cc. 
H 2 O+10 cc. 
m/l 
potassium 
chlorid. 


50 cc. 
n/10 
HCl+30 cc. 
H2O+2O cc. 
m/l 
potassium 
chlorid. 


50 cc. 
n/10 
HC1+20 cc. 
H2O+3O cc. 
m/l 
potassium 
chlorid. 


50 cc. 
n/10 
HCl+10 cc. 
H2O+4O cc. 
m/l 
potassium 
chlorid. 


50 cc. 
n/10 
HC1+50 cc. 
m/l 
potassium 
chlorid. 


50 cc. 
n/10 
HC1+50 cc. 
H 2 0. 


Hrs. in the 
solution. 




Gain 


in parts of one part of gelatin. 




1.40 
6.05 
8.05 
12.40 
23.35 
35.25 
47.05 


1.36 
3.02 
4.11 
5.41 
7.27 
8. 56 
9.58 
I 


1.21 
2.49 
3.42 
4.48 
6.01 
7.06 
8.01 
II 


1.21 
2.39 
3.17 
4.06 
5.40 
6.34 
7.21 
III 


1.03 
2.05 
2.75 
3.57 
4.66 
5.67 
6.51 
IV 


1.00 
1.87 

2.53 
3.32 
4.48 
5.29 
6.11 ' 
V 


1.81 
4.26 
5.86 
6.63 
10.82 
12.79 
14.16 






TABLE XXI 
Gelatin — A cid -{-Salt 






Dry wt. of 
gelatindisc. 


0.763 


0.765 


0.766 


0.772 


0.775 


0.778 


Solution. 


50 cc. 
n/10 
HCl+40 cc. 
H2O+IO cc. 
m/l 
potassium 
citrate. 


50 cc. 
n/10 
HCl+30 cc. 
H2O+2O cc. 
m/l 
potassium 
citrate. 


50 cc. 
n/10 
HC1+20 cc. 
H2O+3O cc. 
m/l 
potassium 
citrate. 


50 cc. 
n/10 
HCl+10 cc. 

H2O+40 cc. 
m/l 
potassium 
citrate. 


50 cc. 
n/10 
HC1+50 cc. 
m/l 
potassium 
citrate. 


50 cc. 
n/10 
HC1+50 cc. 
H 2 0. 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


1.40 
6.05 
8.05 
12.40 
23.35 
35.25 
47.05 


1.11 
1.93 
2.64 
3.39 
4.42 
5.12 
5.57 
I 


1.01 
1.86 
2.46 
3.13 
4.04 
4.67 
5.09 
II 


0.95 
1.68 
2.61 (?) 
2.81 
3.63 
4.15 
4.52 
III 


0.73 
1.25 
1.64 
2.08 
2.80 
3.26 
3.59 
IV 


0.61 
1.02 
1.33 
1.65 
2.21 
2.56 
2.84 
V 


2.20 
4.55 
6.22 
6.93 
11.13 
13.13 
14.61 




ABSORPTION, SECRETION— CELLS AND TISSUES 91 



TABLE XXII 



Gelatin — A cid -{-Salt 



Dry wt. of 
gelatin disc. 


0.778 


0.782 


0.783 


0.788 


0.790 


0.794 


Solution. 


50 cc. 
n/10 
HCl+40 cc. 
H 2 O+10 cc. 
m/1 
potassium 
sulpho- , 
cyanate. 


50 cc. 
n/10 
HCl+30 cc. 
H2O+20 cc. 
m/1 
potassium 
sulpho- 
cyanate. 


50 cc. 
n/10 
HCl+20 cc. 

H2O+30 cc. 

m/1 
potassium 
sulpho- 
cyanate. 


50 cc. 
n/10 
HCl+10 cc. 
HjO+40 cc. 
m/1 
potassium 
sulpho- 
cyanate. 


50 cc. 
n/10 
HC1+50 cc. 
m/1 
potassium 
sulpho- 
cyanate. 


50 cc. 
n/10 
HC1+50 cc. 
H 2 0. 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


1.40 

6.05 
8.05 
12.40 
23.35 
35.25 
47.05 


1.33 
2.68 
3.46 
4.47 
6.28 
7.50 
8.74 

I 


0.86 
1.54 
1.96 
2.54 
3.36 
3.93 
4.56 

II 


0.82 
1.40 
1.65 
1.93 
2.42 
2.56 
2.66 

III 


0.73 
1.25 
1.32 
1.47 
1.85 
1.56 
1.56 

IV 


0.68 
1.07 
1.16 
1.18 
1.43 
1.11 
Tqo sticky 
to weigh 
V 


2.06 
4.61 
6.27 
8.43 
11.49 
13.58 
15.07 



TABLE XXIII 



Gel ati n — A cid +Salt 



Dry wt. of 
gelatindisc. 


0.755 


0.792 


0.755 


0.771 


0.722 


0.750 


Solution. 


50 cc. 
n/10 
HCl+40 cc. 
H2O+IO cc. 
m/1 
potassium 
chlorid. 


50 cc. 
n/10 
HCl+30 cc. 
H2O+2O cc. 
m/1 
potassium 
chlorid. 


50 cc. 
n/10 
HCl+20 cc. 
H2O+30 cc. 
m/1 
potassium 
chlorid. 


50 cc. 
n/10 
HCl+10 cc. 

H2O+40 cc. 

m/1 
potassium 
chlorid. 


50 cc. 
n/10 
HC1+50 cc. 
m/1 
potassium 
chlorid. 


50 cc. 
n/10 
HC1 +50 cc. 
H2O. 


Hrs. in the 
solution. 




Gain i 


n parts of one part of gelatin. 




14.00 
27.35 
36.15 
48.45 
75.35 
144.15 
213.15 


4.5 
5.9 
6.4 
6.8 
7.5 
9.2 
10.3 
I 


3.7 
4.9 
5.3 
5.8 
6.3 
7.9 
8.9 
II 


3.2 
4.2 
4.6 
5.0 
• 5.8 
7.0 
7.8 
III 


3.2 
4.0 
4.5 
4.8 
5.6 
6.9 
7.7 
IV 


3.0 
3.8 
4.2 
4.6 
5.3 
6.4 
7.2 
V 


6.5 
8.6 
9.2 
9.8 
11.0 
12.9 
14.4 



92 



(EDEMA AND NEPHRITIS 



TABLE XXIV 



Gelatin — Acid + Salt 



Dry » of 
gelatin disc. 


0.724 


0.743 


0.723 


0.788 


0.738 


0.740 


Solution. 


50 cc. 
n/10 
HC1+40 cc. 
H 2 O+10 cc. 
m/1 
calcium 
chlorid. 


50 cc. 
n/10 
HC1+30 cc. 
H2O+2O cc. 
m/1 
calcium 
chlorid. 


50 cc. 
n/10 
HCl+20 cc. 
H2O+3O cc. 
m/1 
calcium 
chlorid. 


50 cc. 
n/10 
HCl+10 cc. 
H2O+4O cc. 
m/1 
calcium 
chlorid. 


50 cc. 
n/10 
HC1+50 cc. 
m/1 
calcium 
chlorid. 


50 cc. 
n/10 
HC1+50 cc. 
H 2 0. 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


14.00 
27.35 
36.15 
48.45 
75.35 
144.15 
213.15 


3.8 
3.5 
5.3 
5.6 
6.4 
7.6 
8.5 
I 


2.9 
3.9 
4.4 
4.7 
5.5 
6.8 
7.6 
II 


2.9 
3.7 
4.2 
4.6 
5.4 
6.8 
7.8 
III 


2.3 
3.2 
3.7 
4.1 
5.0 
6.8 
7.9 
IV 


2.4 
3.4 
3.9 
4.4 
5.4 
7.4 
8.7 
V 


6.5 
8.4 
9.2 
9.7 
10.9 
12.9 
14.6 






TABLE XXV 










Gelatin — Acid -{-Salt 






xjry w i. ui 
gelatin disc. 


0.632 


0.690 


0.686 


0.597 


0.700 


0.676 


Solution. 


50 cc. 
n/10 
HC1 +40 cc. 

H2O+IO cc. 
m/1 
sodium 
chlorid. 


50 cc. 

n/10 

HCl+30 cc. 

H2O +20 cc. 
m/1 
sodium 
chlorid. 


50 cc. 
n/10 
HCl+20 cc. 

H2O + 30 cc. 

m/1 
sodium 
chlorid. 


50 cc. 
n/10 
HCl+lOcc. 
H2O +40 oc. 
m/1 
sodium 
chlorid. 


50 cc. 
n/10 
HC1 +50 cc. 
m/1 
sodium 
chlorid. 


50 cc. 
n/10 
HC1 +50 cc. 
H2O. 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


14.00 
27.35 
36.15 
48.45 
75.35 
144.15 
213.15 


5.0 
6.2 
6.6 
7.0 
7.8 
9.1 
10.0 
I 


3.9 
4.9 
5.3 
5.7 
6.3 
7.6 
8.4 
II 


3.5 
4.4 
3.5 (?) 
■ 5.1 
5.6 
6.9 
7.5 
III 


3.5 
4.3 
4.6 
4.9 
5.4 
6.5 
6.9 
IV 


2.8 
3.6 
3.9 
4.2 
4.8 
5.9 
6.6 
V 


7.1 

8~r7 

9.3 
9.8 
10.8 
12.7 
14.2 



ABSORPTION, SECRETION — CELLS AND TISSUES 93 
TABLE XXVI 



Gelatin — Alkali +Salt 



Dry wt. of 
gelatin disc. 


0.799 


0.798 


0.797 


0.787 


0.782 


Solution. 


50 cc. n/10 
NaOH+50cc. 
H 2 0. 


50 cc. n/10 
NaOH+50 cc. 
m/5 
sodium 
acetate. 


50 cc. n/10 
NaOH+50-C 
m/5 
sodium 
bromid. 


50 cc. n/10 
NaOH +50 cc. 
m/5 
sodium 
chlorid. 


50 cc. n/10 
NaOH+50cc. 
m/5 
sodium 
citrate. 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


4.45 
17.00 
24.30 
. 47.30 


3.94 
8.83 
12.38 
melted 


2.71 

6.00 

8.12 
too soft 
to weigh 


3.37 
■ 7.42 

9.83 
too soft 
to weigh 


3.14 

6.91 

9.29 
too soft 
to weigh 


2.22 
4.73 
6.23 
8.65 
much broken 


Dry wt. of 
gelatin disc. 


0.776 


0.770 


0.756 


0.755 


0.754 


Solution. 


50 cc. n/10 
NaOH+50 cc. 
m/5 
sodium 
iodid. 


50 cc. n/10 
NaOH+50 cc. 
m/5 
sodium 
nitrate. 


50 cc. n/10 
NaOH+50 cc. 
m/5 
disodium 
phosphate. 


50 cc. n/10 
NaOH+50 cc. 
m/5 
sodium 
sulphate. 


50 cc. n/10 
NaOH+50cc. 
m/5 
NaK 
tartrate. 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


4.45 
17.00 
24.30 
47.30 


3.34 
7.40 
11.02 
melted 


3.46 
7.58 
10.40 
almost 
melted 


2.41 
4.78 
6.10 
9.11 
good body 


2.95 

6.04 

8.08 
breaks on 
handling 


2.88 
5.95 
7.82 
firmer than 
preceding 



(e) Non-electrolytes do not share with electrolytes their 
marked power of reducing through their presence .the amount 
that gelatin will swell in the solution of any acid or alkali. Figs. 
19, 20 and 21 illustrate this better than words. The upper curve 
of Fig. 19 indicates the amount and rate of swelling of a gelatin 
disc in a pure hydrochloric acid solution. The black circles, 
crosses, squares and triangles just below this curve give the gains 
in weight of gelatin discs kept in equally concentrated hydro- 
chloric acid solutions to which various amounts of ethyl alcohol 
have been added. While present in amounts osmotically more 
than equivalent to the salts added in the previously described 
experiments, there is practically no reduction in the amount of 
swelling of the gelatin discs. The same is true when methyl 



94 



(EDEMA AND NEPHRITIS 



alcohol is added to a hydrochloric acid solution. To avoid 
confusion only one of these curves has been filled in, and the 




whole series has been placed somewhat to the right in the drawing. 
The methyl alcohol series is indicated in white crosses, squares, 
circles and triangles to distinguish it from the ethyl alcohol 



ABSORPTION, SECRETION— CELLS AND TISSUES 95 

series. As readily apparent, the characters practically coincide 
with each other. 




In Fig. 20 is shown the effect of adding various amounts 
of glycerin and urea to a hydrochloric acid solution. The curve 



96 



(EDEMA AND NEPHRITIS 




Figure 21. 



ABSORPTION, SECRETION— CELLS AND TISSUES 97 



for the pure hydrochloric acid solution occupies a position at 
about the middle of the series. The curves marked I, II, III 
and IV show the effect on swelling of adding progressively larger 
amounts of glycerin to the hydrochloric acid solution. Glycerin 
produces a definite decrease in the amount of swelling, though 
as compared with the effect of any electrolyte, it is slight. Urea, 
on the other 16 
hand, distinctly 
favors the swelling 
of gelatin in a 
hydrochloric acid 
solution, and this 
the more the 
higher the con- 
centration of the 
urea. The curves 
marked I', II', III' 
and IV' demon- 
strate this fact. 

Because the 
n o n - electrolytes 
are so comparative- 
ly ineffective in re- 
ducing the swell- 
ing of protein 
colloids in the 
presence of an 
acid many have 
made this state- 
ment read, entire- 
ly without effect. 




Figure 22. 



This is by no means the case, a fact which must be remembered 
for future discussion. The various sugars, for example, have, 
like glycerin, a decided dehydrating effect, especially in the higher 
concentrations. Fig. 21 illustrates this in the case of saccharose, 
which represents the most active of this class of compounds. 

The effect of various non-electrolytes on the swelling of gelatin 
in an alkaline solution is shown in Fig. 22. Only the curve for 
the pure sodium hydroxid has been filled in. As with acids, 
urea again favors the swelling. The addition of ethyl and methyl 



98 



(EDEMA AND NEPHRITIS 



alcohols and glycerin is without effect, for these curves practically 
coincide with that for the pure alkali. In contrast hereto the 
addition of an electrolyte, lithium chlorid, produces a distinct 
diminution in the amount of the swelling. 

The curves of Figs. 19, 20, 21 and 22 have been constructed 
from the experimental data contained in Tables XXVII, XXVIII 
XXIX and XXX respectively. 



TABLE XXVII 
Gelatin — Acid + Non-electrolytes 



Dry wt. of 
gelatin disc. 


0.773 


0.765 


0.756 


0.748 


0.723 


Solution. 


50 cc. n/10 
HC1 +40 cc. 
H 2 O+10 cc. 

2/m 
ethyl alcohol. 


50 cc. n/10 
HC1+30 cc. 
H2O +20 cc. 

2/m 
ethyl alcohol. 


50 cc. n/10 
HC1+20 cc. 
H2O+3O cc. 

2/m 
ethyl alcohol. 


50 cc. n/10 
HC1+50 cc. 

2/m 
ethyl alcohol. 


50 cc. n/10 
HC1+50 cc. 
H 2 0. 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


13.20 
24.45 
67.30 
97.05 
113.35 
162.45 
212.05 
13 days 


6.9 
9.2 
12.5 
13.5 
13.8 
14.4 
14.7 
15.4 
Black 
Circle 


6.7 
9.1 
12.7 
13.8 
14.1 
14.7 
15.0 
15.6 
Black 
Square 


6.8 
8.8 
12.4 
13.5 
13.9 
14.5 
14.8 
15.3 
Black 
Cross 


6.2 
8.7 
12.3 
13.4 
13.9 
14.4 
• 14.7 
15.0 
Black 
Triangle 


7.7 
10.1 
13.2 
14.2 
14.6 
15.1 
15.5 
16.2 



Dry wt. of 
gelatin disc. 


0.733 


0.729 


0.727 


0.724 


Solution. 


50 cc. n/10 
HC1 +40 cc. 

H2O+IO cc. 
2/m 
methyl alcohol. 


50 cc. n/10 
HCl+30cc. 
H 2 +20 cc. 
2/m 
methyl alcohol. 


50 cc. n/10 
HC1+20 cc. 
H2O +30 cc. 
2/m 
methyl alcohol. 


50 cc. n/10 
HC1+50 cc. 
2/m 
methyl alcohol. 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


13.20 
24.45 
67.30 
97.05 
113.35 
162.45 
212.05 
13 days 


7.6 
10.1 
13.1 
14.0 
14.4 
14.9 
15.4 
16.0 
White 
Star 


6.9 
9.4 
12.7 
13.7 
13.9 
14.6 
14.9 
15.5 
White 
Circle 


7.1 
9.4 
12.7 
13.7 
14.1 
14.6 
14.9 
15.4 
White 
Square 


6.7 

9.2 
12.5 
13.5 
13.9 
14.3 
14.1 
15.2 
White 
Triangle 



ABSORPTION, SECRETION— CELLS AND TISSUES 99 



TABLE XXVIII 
Gelatin — A cid + Non-electrolytes 



Dry wt. of 
gelatin disc. 


0.829 


0.872 


0.842 


0.816 


0.810 


Solution. 


50 cc. n/10 
HC1+40 cc. 
H2O+IO cc. 
2/m 
glycerin. 


50 cc. n/10 
HC1+50 cc. 
H 2 O+20 cc. 
2/m 
glycerin. 


50 cc. n/10 
HC1+20 cc. 
H 2 +30 cc. 
2/m 
glycerin. 


50 cc. n/10 
HC1+50 cc. 
2/m 
glycerin. 


50 cc. n/10 
HC1+50 cc. 
H 2 0. 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


13.20 
24.45 
67.30 
97.05 
113.35 
162.45 
212.05 
13 days 


6.6 
9.0 
12.5 
13.6 
13.9 
14.5 
14.8 
15.3 
I 


6.1 

8.2 
12.2 
13.3 
13.7 
14.3 
14.6 
15.1 

II 


5.9 
8.1 
11.7 
12^.8 
13.1 
13.7 
14.0 
14.5 
III 


5.6 
7.8 
11.4 
12.4 
12.7 
13.2 
13.5 
14.0 
IV 


6.9 
9.4 
13.1 
14.2 
14.6 
15.2 
15.6 
17.0 



Dry wt. of 
gelatin disc. 


0.851 


0.848 


0.837 


0.832 


Solution. 


50 cc. n/10 
HC1 +40 cc. 
H2O+IO cc. 
2/m urea. 


50 cc. n/10 
HC1 +30 cc. 
H 2 +20 cc. 
2/m urea. 


50 cc. n/10 
HCl+20cc. 
H 2 +30 cc. 
2/m urea. 


50 cc. n/10 
HC1 +50 cc. 
2/m urea. 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


13.20 
24.45 
67.30 
97.05 
• 113.35 
162.45 
212.05 
13 days 


6.4 
9.1 
13.3 
14.5 
15.1 
15.7 
16.0 
16.8 

r 


7.2 
10.1 
14.7 
16.1 
16.6 
17.4 
17.7 
18.6 

II' 


7.2 
10.2 
15.0 
16.7 
17.3 
18.4 
18.8 
19.5 
III' 


7.3 
10.8 
18.1 
20.7 
21.5 
23.1 
23.7 
24.5 

V 



(/) For purposes of biological application there are introduced 
here a series of experiments showing the effect of various non- 
electrolytes upon ordinary commercial gelatin when no acid or 
alkali has been added from without. 1 

No special comments are necessary upon the results reproduced 
in this paper, obtained by comparing the swelling of gelatin in 
water with the swelling of this same gelatin in, differently con- 



1 Martin H. Fischer and Anne Sykes: Science, 38, 486 (1913); Kolloid- 
Zeitschr., 14, 215 (1914). 



100 



(EDEMA AND NEPHRITIS 



centrated solutions of various non- electrolytes. We used sac- 
charose, levulose, de.trose, methyl alcohol, propyl alcohol, 

TABLE XXIX 



Gelatin — A cid -{-Saccharose 



Dry wt. of 
gelatin disc. 


0.518 


0.515 


0.515 


0.507 


0.502 


0.501 


0.500 


Solution. 


100 cc. 
H 2 


5 cc. n/10 
HC1 
+95 cc. 
H 2 


5 cc. 
n/10 
HC1 
+ 5 cc. 
2/m 
saccharose 

+90 cc. 
. H 2 


5 cc. 
n/10 
HC1 
+30 cc. 
2/m 
saccharose 
+65 cc. 
H 2 


5 cc. 
n/10 
HC1 

+50 cc. 
2/m 
saccharose 
+45 cc. 
H 2 


5 cc. 

n/10 

HC1 
+75 cc. 

2/m 
saccharose 
+20 cc. 

H 2 


5 cc. 
n/10 
HC1 
+95 cc. 
2/m 
saccharose 


Hrs. in the 
Solution. 


Gain in parts of one part of gelatin. 


18.45 
26.30 
42.00 
50.45 


5.28 
6.27 
9.88 
12.26 


28.36 
47.54 
In sol 


21.38 
41.71 
ution 


15.90 
31.90 
58.17 
65.07 


9.72 
17.27 
36.25 
51.75 


3.62 
7.18 
13.50 
17.50 


1.89 
3.98 
6.08 
7.78 







TABLE XXX 
Gelatin — A Ikali + Non-electrolytes 



Dry wt. of 
gelatindisc. 


0.710 


0.712 


0.714 


0.715 


0.716 


0.705 


Solution. 


50 cc. 
n/10 
NaOH 
+50 cc. 
m/5 
LiCl. 


50 cc. 

n/10 
NaOH 
+50 cc. 
2/5 m 

urea. 


50 cc. 
n/10 
NaOH 
+50 cc. 
2/5 m 
glycerin. 


50 cc. 

n/10 
NaOH 
+50 cc. 
2/5 m 

ethyl 
alcohol. 


50 cc. 

n/10 
NaOH 
+50 cc. 
2/5 m 
methyl 
alcohol. 


50 cc. 
n/10 
NaOH 
+50 cc. 
H 2 0. 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


3.15 
16.15 
24.00 


3.46 
9.07 
9.98 


3.70 
12.45 
13.57 
Melting 
Black circle 


3.71 
11.53 
15.79 

White circle 


3.70 
11.79 
15.29 

Triangle 


3.64 
11.51 
15.60 

Square 


3.80 
11.70 
15.82 



propylene glycol and acetone. The presence of all these non- 
electrolytes reduces the amount of the swelling, and this the 
more the higher the concentration of the added substance. 



ABSORPTION, SECRETION— CELLS AND TISSUES 101 



When these curves are paralleled with those available on the 
effect of different electrolytes (salts) on the swelling of gelatin 




in the presence of acid one is impressed with the fact, when equi- 
molar or osmotically equivalent solutions are compared, that 
the non-electrolytes are relatively most powerful in their de- 



102 



(EDEMA AND NEPHRITIS 



hydrating effects in the higher concentrations, while of the elec- 
trolytes the reverse is true. Thus, in even low concentrations 




the salts produce a great dehydrating effect, but with every unit 
increase in concentration the degree of shrinkage becomes pro- 
gressively less. Just the opposite holds for the non-electrolytes, 



ABSORPTION, SECRETION— CELLS AND TISSUES 103 



where low concentrations are comparatively ineffective, but 
where an unexpectedly great dehydrating effect is observed 
as the concentration rises. 




But while all these non-electrolytes reduce the swelling of 
gelatin there exist some interesting quantitative differences 
between them. As shown in Figs. 23, 24 and 25 and the corre- 



104 



(EDEMA AND NEPHRITIS 



TABLE XXXI 



Gelatin — Saccharose 



Dry wt. of 
gelatin disc. 


0.726 


0.721 


0.722 


0.723 


0.724 


0.725 


0.726 


Solution. 


100 cc. 

H 2 


10 cc. 

2/m 
saccharose 
+90 cc. 
H 2 


20 cc. 
2/m 
saccharose 
+80 cc. 
H2O 


30 cc. 
2/m 
saccharose 
+70 cc. 
H 2 


50 cc. 
2/m 
saccharose 
+50 cc. 
H2O 


75 cc. 
2/m 
saccharose 
+25 oc. 
HjO 


100 cc. 

2/m 
saccharose 


Hrs. in the 
Solution. 


Gain in parts of one part of gelatin 


2.45 
17.15 
25.00 
42.15 
65. 15 


1.51 
5.61 
6.65 
9.51 
11.69 


0.81 
5.03 
6.11 
8.29 
9.36 


1.13 
4.56 
5.59 
7.83 
9.34 


1.03 
4.01 
4.97 
7.21 
8.74 


0.78 
2.69 
3.41 
5.18 
6.51 


0.52 
1.43 
1.76 
2.65 
3.53 


0.26 
0.65 
0.90 
1.15 
1.54 



TABLE XXXII 
Gelatin — Levulose 



Dry wt. of 
gelatin disc. 


0.732 


0.744 


0.750 


0.759 


0.797 




0.797 


0.797 


Solution. 


100 cc. 
H 2 


10 cc. 

2/m 
levulose 
+90 cc. 

H 2 


20 cc. 

2/m 
levulose 
+80 cc. 

H2O 


30 cc. 

2/m 
levulose 
+70 cc. 

H2O 


50 cc. 

2/m' 
levulose 
+50 cc. 

H2O 




100 cc. 

2/m 
levulose 


100 cc. 

4/m 
levulose 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 

Hours. 


7.00 
22.30 
31.00 
46.30 
55.00 


2.90 
6.01 
6.77 
8.44 
8.77 


2.90 
5.80 
6.47 
7.97 
8.07 


2.78 
5.67 
6.25 
7.87 
8.17 


2.71 
5.38 
6.23 
7.71 
8.11 


2.55 
5.29 
6.03 
6.82 
8.27 


3.50 
19.00 
28.20 
43.50 


1.16 
3.74 
4.89 
7.24 


0.46 
1.13 
1.43 
2.11 



TABLE XXXIII 
Gelatin — Dextrose 



Dry weight of 
gelatin disc. 


0.678 


0.699 


0.699 


0.713 


Solution. 


100 cc. H 2 


10 cc. 2/m 

dextrose 
+90 cc. H 2 


20 cc. 2/m 

dextrose 
+80 cc. H2O 


30 cc. 2/m 

dextrose 
+70 cc. H 2 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


7.30 
23.15 
31.15 
47.15 
55.45 " 


2.44 
5.85 
6.51 
8.26 
8.72 


2.76 
5.82 
6.46 
8.09 
8.19 


2.75 
5.61 
6.31 
7.92 
8.17 


2.27 
4.97 
5.71 
7.29 
7.62 



ABSORPTION, SECRETION— CELLS AND TISSUES 105 

sponding Tables XXXI, XXXII and XXXIII, the various 
sugars all reduce the swelling of gelatin, but at the same con- 




centration saccharose is far more powerful in this regard than 
either levulose or dextrose, which produce approximately equal 



106 



OEDEMA AND NEPHRITIS 



degrees of dehydration. This is readily apparent on comparing 
curves I, II, III, IV and VI of Fig. 23 with the corresponding 




curves I, II, III, IV and V of Fig. 24, or the first three of these 
with curves I, II and III of Fig. 25. 

Methyl and propyl alcohols, propylene glycol and acetone 



ABSORPTION, SECRETION— CELLS AND TISSUES 107 



all approximate the monosaccharids in the degree of dehydra- 
tion which they bring about. Only in very high concentra- 




tions are they able to bring about a dehydration which sac- 
charose brings about in much lower ones, as readily apparent 
when Figs. 26, 27, 28 and 29 are compared with Fig. 23. 



106 



(EDEMA AND NEPHRITIS 



Tables XXXIV, XXXV, XXXVI and XXXVII contain the 
experimental data from which Figs. 26 to 29 have been con- 
structed. 




(g) The absorption and secretion of water by gelatin represent 
in large part reversible processes. This fact is brought out in 



ABSORPTION, SECRETION— CELLS AND TISSUES 109 



TABLE XXXIV 



Gelatin — Methyl Alcohol 



Dry weight of 
gelatin disc. 


0.747 


0.729 


0.729 


0.739 


0.744 


0.746 


0.746 


Solution. 


100 cc. 
H 2 


2 cc. 

10/m 
methyl 
alcohol 
+98 cc. 

H2O 


5 cc. 

10/m 
methyl 
alcohol 
+95 cc. 

H2O 


10 cc. 

10/m 
methyl 
alcohol 
+90 cc. 
H 2 


20 cc. 

10/m 
methyl 
alcohol 
+80 cc. 
H2O 


50 cc. 

10/m 
methyl 
alcohol 
+50 cc. 

H2O 


100 cc. 
10/m 
methyl 
alcohol 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


5.30 
21.30 
29.30 
48.00 
53.30 


2.95 
6.32 
7.12 
8.54 
9.52 


2.85 
6.27 
7.01 
8.30 
8.21 


2.57 
5.87 
6.63 
7.83 
8.39 


2.55 
5.50 
6.27 
7.43 
7.87 


2.36 
3.15 
5.50 
6.45 
6.76 


1.60 
3.12 
3.58 
4.09 
4.29 


0.93 
1.69 
1.97 
2.14 
2.19 


TABLE XXXV 
Gelatin — Propyl Alcohol 


Dry weight of 
gelatin disc. 


0.708 


0.681 


0.683 


0.683 


0.689 


0.690 


0.707 


Solution. 


100 cc. 
H2O 


2 cc. 

10/m 
propyl 
alcohol 
+98 cc. 
H2O 


5 cc. 
10/m 
propyl 
alcohol 
+95 cc. 

H2O 


10 cc. 

10/m 
propyl 
alcohol 
+90 cc. 
H 2 


20 cc. 

10/m 
propyl 
alcohol 
+80 cc. 

H 2 


50 cc. 

10/m 
propyl 
alcohol 
+50 cc. 
H2O 


100 cc. 
10/m 
propyl 
alcohol 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


5.00 
20.00 
29.00 
46.00 


2.85 
7.28 
8.71 
11.16 


2.72 
7.51 
8.85 
10.39 


2.59 
7.21 
8.83 
10.37 


2.46 
6.74 
8.07 
8.54 


2.08 
4.25 
5.70 
7.61 


1.19 
2.15 
2.75 
3.43 


0.28 
0.51 
0.55 
0.58 



Fig. 30 and Table XXXVIII, from which it is constructed. 
When a gelatin disc is transferred from a pure hydrochloric acid 
or sodium hydroxid solution into an equally concentrated one 
containing a salt, a prompt fall in the absorption curve is noted. 
A rise in the curve follows the reverse process. A further fact 
of interest in Fig. 30 is that at the same concentration potassium 
citrate inhibits the swelling of gelatin in a hydrochloric acid 
solution more than in an equinormal sodium hydroxid solution. 



110 



(EDEMA AND NEPHRITIS 



TABLE XXXVI 



Gelatin — Propylene Glycol 



Dry wt. of 
gelatin disc. 


0.718 


0.755 


0.752 


0.748 


0.747 


0.743 


733 


0.709 


Solution. 


100 cc. 
H 2 


2 cc. 
10/m 
propy- 
lene 
glycol 
+98 cc. 
H2O 


5 cc. 
10/m 
propy- 
lene 
glycol 
+95 cc. 
H 2 


10 cc. 
10 m 
propy- 
lene 
glycol 
+90 cc. 
H 2 


20 cc. 
10/m 
propy- 
lene 
glycol 
+80 cc. 
H 2 


30 cc. 

10/m 

propy- 
lene 

glycol 
+70 cc. 
H 2 


50 cc. 

10/m 

propy- 
lene 

glycol 
+50 cc. 
H 2 


80 cc. 
10/m 
propy- 
len 

glv 1 
+20 cc. 
H 2 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


6.15 
20.45 
29.45 
45.00 
54.30 


2.49 
4.60 
5.30 
6.82 
7.33 


2.19 
4.49 
5.98 
6.26 
7.14 


2.07 
4.36 
4.85 
6.11 
6.69 


1.59 
3.43 
3.91 
4.97 
5.47 


1.36 
3.06 
3.53 
4.59 
5.00 


1.09 
2.32 
2.85 
3.72 
4.04 


0.89 
1.61 
1.79 
2.86 
3.17 


0.40 
0.74 
0.92 
1.43 
1.46 



TABLE XXXVII 
Gelatin — A cetone 



Dry weight of 
gelatin disc. 


0.808 


0.808 


0.807 


0.810 


0.811 


Solution. 


100 cc. H 2 0. 


2 cc. 10/m 
acetone 
+98 cc. H 2 0. 


5 cc. 10/m 

acetone 
+95 cc. H 2 0. 


10 cc. 10/m 

acetone 
+90 cc. H 2 0. 


20 cc. 10/m 

acetone 
+80 cc. H2O. 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


16.00 
25.30 
39.30 
49.15 
66.00 


4.06 
5.59 
7.49 
8.39 
10.39 


3.72 
5.05 
6.55 
7.43 
9.27 


3.56 
4.99 
6.48 
7.20 
8.44 


3.37 
4.78 
6.15 
6.69 
7.57 


3.18 
4.28 
5.78 
6.10 
6.60 



(h) There are other substances besides acids which will increase 
the amount of water that gelatin can hold. First to be men- 
tioned are the salts of the alkali metals. As first noted by Franz 
Hofmeister such salts as the chlorids, bromids and iodids of 
sodium, potassium and lithium increase the absorption of water 
by pure gelatin. This matter is verified for sodium chlorid in 
Fig. 31 and Table XXXIX, which contains the experimental * 
details. In paragraph (e) above, urea was found to be a sub- 



ABSORPTION, SECRETION— CELLS AND TISSUES 111 





/ \ HCl+Salt 




/ NaOH J 




/ /\* Salt 1 ^ ' 


HCl / 






/ NaOH/ 1 




/NaOH / / HCl 




/ / /* 


/ / 


NaOH -f^^alt / 




HCl+Sal-t^j/ 




GELATIN 



4 8 12 16 20 34 

Hours 

Figure 30. 



TABLE XXXVIII 
Gelatin 



Dry weight of 
gelatin disc. 


I 

0.705 


II 

0.705 


III 

0.722 


IV 
0.721 


Solution. 


50 cc. n/10 
NaOH +50 cc. 
H 2 0. 


50 cc. n/10 
NaOH +50 cc. 
m/5 K citrate. 


50 cc. n/10 
HCl +50 cc. 
H 2 0. 


50 cc. n/10 
HCl +50 cc. 
m/5 K citrate. 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


3.15 
16.15 


3.80 
11.70 


2.74 
7.39 


5.44 
16.74 


2.26 
5.02 




Disc I is put into Solution II; Disc II into Solution I. 
Disc III is put into Solution IV; Disc IV into Solution III. 


18.25 
20.35 
24.00 


10.49 
10.63 
11.21 


9.85 
11.19 
11.34 


15.20 
14.70 
14.72 


7.64 
12.26 
14.77 



112 



(EDEMA AND NEPHRITIS 



stance which when added to an acid solution would increase 
the swelling of gelatin. Urea will do this also in neutral solu- 




tion as shown in Fig. 32 and Table XL, from which this is con- 
structed. When the urea is sufficiently concentrated the gelatin 
goes into solution. Pyridin represents another substance which 



ABSORPTION, SECRETION— CELLS AND TISSUES 113 



TABLE XXXIX 

Gelatin — NaCl . 



Dry weight of 
gelatin disc. 


0.715 


0.712 


0.701 


0.694 


Solution 


100 cc. H 2 


10 cc. m/1 NaCl 
+75 cc. H 2 Q 


25 cc. m/1 NaCl 
+75 cc. H2O 


50 cc. m/1 NaCl 
+50 cc. H2O 


Hours in the 
solution 


Gain in parts of one part of gelatin 


5.30 
20.30 
29.30 
43.30 . 
52.00 
67.00 
76.00 


2.43 
4.59 
5.26 
6.68 
7.32 
9.02 
10.98 


2.83 
6.04 
6.71 
8.60 
9.19 
11.47 
13.31 


2.98 
6.54 
7.33 
9.59 
10.20 
12.60 
13.70 


3.12 
6.91 
7.77 
9.60 
10.12 
13.67 
15.08 



TABLE XL 

Gelatin — Urea 



Dry weight of 
gelatin disc. 


0.786 


0.782 


0.793 


0.796 


0.759 


0.760 


0.788 


Solution 


100 cc. 
H2O 


2 cc. 
10/m 
urea 
+98 cc. 
H2O 


5 cc. 
10/m 
urea 
+95 cc. 
H2O 


10* cc. 
10/m 
urea 

+90 cc. 
H2O 


20 cc. 
10/m 
urea 

+80 cc. 
H2O 


50 cc. 
10/m 

urea 
+50 cc. 

H2O 


100 cc. 
10/m 
urea 


Hours in the 
solution 


Gain in parts of one part of gelatin 


5.30 
21.45 
45.15 


2.60 
5.93 
7.97 . 


2.67 
6.83 
9.97 


2.88 
8.17 
11.36 


3.26 
10.65 
14.45 


2.96 
Complete 
solution 


1 

Complete 
solution 



TABLE XLI 

Gelatin — Pyridin 



Dry weight of 
gelatin disc. 


0.780 


0.780 


0.781 


0.783 


0.783 


0.783 


0.784 


0.785 


Solution 


100 cc. 
H2O 


0.1 cc. 

5/m. 
pyridin 
+ 100 cc. 

H2O 


0.2 cc. 

5/m 
pyridin 
+ 100 cc. 

H2O 


0.5 cc. 

5/m 
pyridin 
+ 100 cc. 

H2O 


1 cc. 

5/m 
pyridin 
+99 cc. 

H2O 


2 cc. 

5/m 
pyridin 
+98 cc. 

H2O 


3 cc. 

5/m 
pyridin 
+97 cc. 

H2O 


5 cc. 

5/m 
pyridin 
+95 cc. 

H2O 


Hours in the 
solution. 


Gain in parts of one part of gelatin 


16.45 
38.45 
46.30 
62.30 
73.00 


3.75 
6.12 
6.51 
8.00 
9.29 


3.77 
6.43 
. 6.87 
8.48 
9.61 


4.01 

6.73 
7.23 
8.96 
9.85 


4.10 
6.98 
7.51 
9.16 
10.45 


4.44 
7.59 
8.22 
10.12 
13.23 


4.63 
8.56 
9.28 
11.91 
13.48 


4.84 
9.85 
11.77 
14.19 
16.60 


5.00 
10.40 
11.52 
15.63 
18.38 



114 (EDEMA AND NEPHRITIS 

has activities in this direction, as shown in Fig. 33 and Table 
XLI. 




Some of the amins also belong in the group with urea and pyri- 
din, but they are so intensely alkaline in watery solution that 
special pains need to be taken to eliminate first this alkaline effect 



ABSORPTION, SECRETION— CELLS AND TISSUES 



115 



before their more specific hydrating action becomes evident. 
Hans Handovsky first noted the hydrating effects of the amins 




upon blood proteins. The swelling effects of different concen- 
trations of ethylamin upon gelatin are illustrated in Fig. 34 
and Table XLII. 

(i) As previously emphasized for fibrin, the hydration induced 



116 



(EDEMA AND NEPHRITIS 




Figure 34. 



ABSORPTION, SECRETION— CELLS AND TISSUES 117 



TABLE XLII 



Gelatin — Ethylamin 



Dry weight of 
gelatin disc. 


0.793 


0.800 


0.800 


0.800 


0.802 


0.802 


Solution 


100 cc. 
H 2 


0. 1 cc. 5/m 
ethylamin 
+99.9 cc. 
H2O 


0.2 cc. 5/m 
ethylamin 
+99.8 cc. 
H2O 


0.3 cc. 5/m 
ethylmain 
+99.7 cc. 
H2O 


0. 5 cc. 5/m 
ethylamin 
+99 . 5 cc. 
H2O 


0.75cc.5/m 
ethylamin 
+99.25 cc. 
H2O 


Hours in the 
solution 


Gain in parts of one part of gelatin 


15.00 
25.00 
39.00 


4.80 
6.04 
6.25 


10.25 
10.56 
15.67 


12.26 
15.83 
21.30 


14.76 
17.93 
23.15 


17.66 
21.10 
27.66 


18.85 
23.25 
31.72 






I 


II 


III 


IV 


V 



through urea, pyridin or the amins is of a type different from that 
produced through (acids or) alkalies. As shown in paragraph (e) 
above and again in Fig. 35 and Table XLIII an acid does not 
decrease the swelling effects of urea — the effects of the two sub- 
stances are compounded. The same is true for the addition of 
sodium chlorid to a urea solution. Instead of reducing the swell- 
ing, as would be the case did urea act merely as an alkali, Fig. 
36 and Table XLIV show that the hydrating effect of pure sodium 
chlorid upon gelatin is merely added to that produced by urea. 
On the other hand, various non-electrolytes, such as the sugars, 
reduce a urea hydration markedly, while, as noted above, they 

TABLE XLIII 



Gelatin — Urea-\-HCl 



Dry weight of 
gelatin disc. 


0.553 


0.553 


0.556 


0.557 


0.558 


Solution 


100 cc. 
H2O 


20 cc. 5/m 

urea 
+80 cc. H2O 


20 cc. 5/m 

urea 
+3 cc. n/10 
HC1 +77 cc. 

H2O 


20 cc. 5/m 

urea 
+4 cc. n/10 
HC1 +76 cc. 

H2O 


20 cc. 5/m 

urea 
+5 cc. n/10 
HC1+75 cc. 

H2O 


Hours in the 
solution 


Gain in parts of one part of gelatin 


18.15 
26.30 
42.00 


5.18 
6.36 
9.41 


9.82 
13.52 
35.16 


14.08 
17.00 

Complet 


20.54 
37.79 
e solution 


34.84 
Complete 
solution 



118 



(EDEMA AND NEPHRITIS 




Figure 35. 



ABSORPTION, SECRETION— CELLS AND TISSUES 119 



are relatively ineffective in the case of an acid or alkali hydra- 
tion. The effect of dextrose on urea hydration is illustrated in 
Fig. 37 and Table XLV, from which it is drawn. 




Remarks similar to those made for urea may be made for 
pyridin except that pyridin shows distinctly alkaline properties. 
The effects of an electrolyte like sodium chlorid in reducing the 



120 



(EDEMA AND NEPHRITIS 



TABLE XLIV 



Gelatin — Urea + NaCl 



Dry weight of 
gelatin disc. 


0.792 


0.787 


0.786 


0.773 


Solution. 


20 cc. 5/m urea 
+80 cc. H 2 


20 cc. 5/m urea 
+10 cc. m/1 

NaCl 
+70 cc. H 2 


20 cc. 5/m urea 
+25 cc. m/1 

NaCl 
+55 cc. H 2 


20 cc. 5/m urea 
+50 cc. m/1 

NaCl 
+30 cc. H 2 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


5.15 
20.15 
29.15 
43.15 
52.00 


2.53 
6.54 
7.73 
11.03 
12.85 


3.05 
7.65 
9.03 
12.64 
13.87 


3.50 
9.02 
10.80 
14.54 
17.41 


3.32 
8.93 
10.52 
14.91 
17.75 



TABLE XLV 

Gelatin — Urea + Dextrose 



Dry weight of 
gelatin disc. 


0.812 


0.812 


0.812 


0.812 


0.814 


Solution. 


20 cc. 5/m 

urea 
+80 cc. H 2 


20 cc 5/m 

urea 
+ 5 cc. 2/m 

dextrose 
+75 cc. H 2 


20 cc. 5/m 

urea 
+ 10 cc. 2/m 

dextrose 
+70 cc. H 2 


20 cc. 5/m 

urea 
+25 cc. 2/m 

dextrose 
+55 cc. H 2 


20 cc. 5/m 

urea 
+50 cc. 2/m 

dextrose 
+30 cc. H 2 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


20.30 
25.30 
40.30 
50.00 


9.15 
10.52 
14.73 
16.27 


9.01 
10.29 
14.66 
16.25 


8.56 
9.78 
13.87 
15.49 


7.10 
8.18 
11.89 
13.38 


5.88 
6.81 
10.17 
11.65 



swelling of gelatin in a pyridin solution are shown in Fig. 38 and 
Table XLIV. The slightly better effects of an osmotically equiva- 
lent non-electrolyte (dextrose) are shown in Fig. 39 and Table 
XLVII. 

That the hydrating effects of an amin are largely due to the 
pure alkali formed on dissociation of the amin in water is proved 
by such a series of observations as shown in Table XL VIII in 
which hydrochloric acid is added to an ethylamin solution. As 
shown in the columns marked II and III, the addition of the acid 
produces a marked inhibition of the swelling as seen in the pure 
amin solution. If, however, an amount of acid is added beyond 
that necessary for neutralization the hydrating effects of the pure 



ABSORPTION, SECRETION — CELLS AND TISSUES 121 

acid become apparent, as shown in the columns marked IV, V, VI, 
VII and VIII. 




The reducing effects of an electrolyte like sodium chlorid upon 
the hydration produced in gelatin through ethylamin is illus- 
trated in Fig. 40 and Table XLIX. The ethylamin has, however, 



122 



(EDEMA AND NEPHRITIS 



an action due to something besides the effects of the pure alkali 
formed upon dissociation for Fig. 41 and Table L show the non- 




2 ~~ " 2 »q 



electrolyte used, namely, dextrose, to have an effect larger than 
anticipated. 

It is well in concluding this section to say a word regarding 



ABSORPTION, SECRETION— CELLS AND TISSUES 123 
TABLE XLVI 



Gelatin — Pyridin -j- NaCl 



Dry weight of 
gelatin disc. 


0.793 


0.795 


0.812 


0.812 


0.812 


0.816 


0.817 


Solution 


100 cc. 
H2O 


5 cc. m/1 
+95 cc. 

H-0 


5 cc. m/1 
pyridin 
+5 cc. 
m/1 
NaCl 
+90 cc. 
H2O 


5 cc. m/1 
pyridin 
+ 10 cc. 
m/1 
NaCl 
+85 cc. 
H2O 


5 cc. m/1 
pyridin 
+20 cc. 
m/1 
NaCl 
+75 cc. 
H2O 


5 cc. m/1 
pyridin 
+30 cc. 
m/1 
NaCl 
+65 cc. 
H 2 


5 cc. m/1 
pyridin 
+50 cc. 
m/1 
NaCl 
+45 cc. 
H2O 


Hours in the 
solution 


Gain in parte of one part of gelatin 


18.00 
26.30 
42.00 
51.00 
66.00 


6.92 
8.33 

10.01 
9.72 

10.06 


12.35 
15.84 
20.36 
21.28 
23.25 


9.04 
10.92 
13.35 
13.93 
15.04 


9.55 
11.74 
14.25 
14.81 
15.90 


9.99 
12.31 
15.35 
15.97 
17.37 


10.68 
13.30 
16.85 
17.68 
19.89 


10.17 
13.21 
17.69 
18.78 
21.16 








I 


II 


III 


IV 


V 



TABLE XLVII 
Gelatin — Pyridin -{-Dextrose 



Dry weight of 
gelatin disc. 


0.793 


0.795 


0.792 


0.790 


0.767 


0.736 


0.736 


Solution. 


100 cc. 
H 2 


5 cc. m/1 
pyridin 
+95 cc. 
H 2 


5 cc. m/1 
pyridin 
+ 5 cc. 

2/m 
dextrose 
+90 cc. 

H 2 


5 cc. m/1 
pyridin 
+10 cc. 

2/m 
dextrose 
+85 cc. 

H 2 


5 cc. m/1 
pyridin 
+20 cc. 

2/m 
dextrose 
+75 cc. 

H 2 


5 cc. m/1 
pyridin 
+30 cc. 

2/m 
dextrose 
+65 cc. 

H 2 


5 cc. m/1 
pyridin 
+50 cc. 

2/m 
dextrose 
+45 cc. 

H 2 


Hours in the 
solution. 




Gain in parts of one part of gelat 


n. 




18.00 
26.30 
42.00 
51.00 
66.00 


6.92 
8.33 

10.01 
9.72 

10.06 


12.35 
15.84 
20.36 
21.28 
23.25 


11.60 
14.46 
18.46 
18.85 
17.72 


10.32 
13.12 
16.94 
17.65 
19.28 


9.24 
11.77 
15.09 
15.78 
17.13 


8.79 
10.92 
13.69 
14.32 
15.63 


6.67 
8.29 
10.53 
11.18 
12.62 



the similarities and the differences to be noted between the swelling 
of fibrin and the swelling of gelatin. The two behave similarly 
in that both swell more in the solutions of acids and alkalies than 
in water; both swell to different degrees in equinormal solutions 
of different acids or alkalies, and the order in which these acids 



124 



(EDEMA AND NEPHRITIS 



and alkalies are effective is much the same; the swelling of both 
in either acid or alkaline solutions is markedly inhibited through 
the presence of electrolytes, and this the more the higher the 




Figure 39. 

concentration of the electrolytes. In contrast to the action of 
the electrolytes, the non-electrolytes are comparatively ineffective 
in this regard. 



ABSORPTION, SECRETION— CELLS AND TISSUES 125 




Hours 8 16 24 " 32 

FlGUEE 40. 



126 



(EDEMA AND NEPHRITIS 




Figure 41. 



ABSORPTION, SECRETION — CELLS AND TISSUES t 127 



TABLE XLVIII 



Gelatin — Ethylamin -\-HCl 



Dry weight of 
gelatin disc. 


0.743 


0.744 


0.747 


0.749 


0.750 


Solution 


100 cc. H 2 


5 cc. m/1 
ethylamin 
+95 cc. H2O 


5 cc. m/1 
ethylamin 

+25 cc. 
n/10 HC1 
+70 cc. H2O 


5 cc. m/1 
ethylamin 

+50 cc. 
n/10 HC1 
+45 cc. H2O 


5 cc. m/1 
ethylamin 

+60 cc. 
n/10 HC1 
+35 cc. H2O 


Hours in the 
solution 


Gain in parts of one part of gelatin 


16.30 
24.30 
39.00 
48.00 
63.00 


4.80 
5.54 
6.57 
6.84 
8.45 


18.30 
20.85 
22.84 
22.60 
21.93 


9.33 
10.83 
12.23 
12.33 
12.36 


8.95 
10.74 
13.28 
13.85 
14.67 


14.85 
18.98 
22.72 
25.17 
27.05 






I 


II 


III 


IV 



Dry weight of 
gelatin disc. 


0.750 


0.752 


0.753 


0.753 


Solution 


5 cc. m/1 
ethylamin 

+70 cc. 
n/10 HC1 
+25 cc. H2O 


5 cc. m/1 
ethylamin 

+80 cc. 
n/10 HC1 
+15 cc. H2O 


5 cc. m/1 
ethylamin 

+90 cc. 
n/10 HC1 
+5 cc. H2O 


1 cc. 5/m 
ethylamin 

+99 cc. 
n/10 HC1 


Hours in the 
solution 


Gain in parts of one part of gelatin 


16.30 
24.30 
39.00 
48.00 
63.00 


16.73 
20.64 
26.88 
29.26 
33.06 


16.73 
20.76 
27.05 
29.22 
33.50 


15.87 
19.62 
24.71 
27.46 
33.36 


15.00 
18.07 
23.80 
25.70 
30.75 




V 


VI 


VII 


VIII 



Urea and pyridin are representative of another class of sub- 
stances which increase the power of both fibrin and gelatin to 
swell, but this type of increased hydration, while not affected by 
salts is markedly reduced through various non-electrolytes such 
as the sugars. 

There exist, on the other hand, certain differences between 
the swelling of fibrin and the swelling of gelatin. These are 
for the most part of a quantitative nature. Gelatin is able to 
absorb under optimal conditions about sixty-five times its weight 
in water. With fibrin I have obtained values up to forty times 
its weight in absorbed water. While fibrin swells more in alkaline 



128 (EDEMA AND NEPHRITIS 

TABLE XLIX 
Gelatin — Ethylamin +NaCl 



Dry weight of 
gelatin disc. 


0.725 


0.726 


0.726 


0.727 


0.728 


0.728 


0.728 


Solution 


100 cc. 
H 2 


5 cc. m/1 
ethylamin 
+95 cc. 
H2O 


5 cc. m/1 
ethylamin 

+5 cc. 
m/1 NaCl 

+90 cc. 
H2O 


5 cc. m/1 
ethylamin 

+ 10 cc. 
m/1 NaCl 
+85 cc. 
H2O 


5 cc. m/1 
ethylamin 

+20 cc. 
m/1 NaCl 

+75 cc. 
H2O 


5 cc. m/1 
ethylamin 

+30 cc. 
m/1 NaCl 

+65 cc. 
H2O 


5 cc. m/1 
ethylamin 

+50 cc. 
m/1 NaCl 
+45 cc. 
H2O 


Hours in the 
solution 


Gain in parts of one part of gelatin 


19.00 
27.30 
43.30 
51.00 
66.00 


7.49 
8.71 
10.16 
10.69 
12.38 


30.85 
36.02 
38.55 
38.28 
37.58 


15.10 
17.92 
22.18 
24.08 
26.91 

I 


14.29 
16.97 
21.52 
23.19 
25.18 

II 


13.33 
15.87 
20.55 
22.61 
24.76 

III 


12.50 
15.28 
18.47 
20.82 
22.61 

IV 


10.54 

13.18 

16.97 

19.02 
Complete 
solution 
V 


TABLE L 
Gelatin — Ethylamin -{-Dextrose 


Dry weight of 
gelatin disc. 


0.725 


0.726 


0.732 


0.732 


0.733 


0.734 


0.735 


Solution 


100 cc. 
H2O 


5 cc. m/1 
ethylamin 
+95 cc. 
H2O 


5 cc. m/1 
ethylamin 
+5 cc. 
2/m 
dextrose 
+90 cc. 
H2O 


5 cc. m/1 
ethylamin 
+ 10 cc. 

2/m 
dextrose 
+85 cc. 
H2O 


5 cc. m/1 
ethylamin 
+20 cc. 

2/m 
dextrose 
+75 cc. 
H2O 


5 cc. m/1 
ethylamin 
+30 cc. 

2/m 
dextrose 
+65 cc. 
H2O 


5 cc. m/1 
ethylamin. 
+50 cc. 

2/m 
dextrose 
+45 cc. 
H2O 


Hours in the 
solution 


Gain in parts of one part of gelatin 


19.00 
27.30 
43.30 
51.00 
66.00 


7.49 
8.71 
10.16 
10.69 
12.38 


30.85 
36.02 
38.55 
38.25 
37.58 


24.62 
28.91 
33.25 
33.37 
34.97 


22.34 
26.39 
30.78 
30.99 
32.25 


18.26 
22.22 
26.46 
26.54 
28.60 


16.27 
20.09 
23.70 
24.80 
26.26 


11.42 
14.24 
17.70 
17.92 
19.72 



solutions than in equally concentrated acid solutions, gelatin does 
the reverse. This may, however, be only a seeming difference, 
because of the usual acid content of the commercial gelatins, and 
the consequent formation of salts when they are made to swell in 
alkaline solutions. Fibrin attains its maximal swelling in con- 
centrations of acid which are much below those necessary to pro- 



ABSORPTION, SECRETION— CELLS AND TISSUES 129 



duce the maximum amount of swelling in gelatin, and higher con- 
centrations of electrolytes are necessary to reduce markedly the 
swelling of gelatin in acid solutions than are necessary in the case 
of fibrin. On the other hand, urea and pyridin seem able to 
induce a relatively higher hydration in gelatin than in fibrin. All 
these statements must, however, not be taken too strictly, for 
depending upon the history of their preparation, etc., the gelatins 
differ widely from each other. 

Such similarities and differences in the behavior of different 
colloids toward the same external conditions demand detailed 
study, for they are of the utmost biological importance. Pro- 
toplasm consists of a mixture of many different colloids. Not 
only are different colloids found in the ; same cell, but essentially 
different colloids form the basis ^of* different tissues (bone, car- 
tilage, muscle, connective tissue, parenchymatous organs, central 
nervous system). It is at once apparent, therefore, that not 
only so far as water absorption and secretion is concerned, but 
so far as any physiological reaction dependent upon the colloid 
constitution of living matter is concerned, a single variation 
in internal or external conditions may be followed by quite a 
different response either qualitatively or quantitatively, not 
only by different tissues, but by different parts of the same tissue 
or even the same cell. In a study of the behavior of different 
colloids toward the sanie. group bf external conditions we may 
therefore hope to discover muchr to aid us in our attempt to 
analyze- the apparently- limitless in the reactions of 

protoplasm to various external " stimuli^ 

4. Observations on the Swelling of Gluten. 

The absorption of water by proteins has recently received 
interesting elaboration by the work of Fred W. Upson and J. W. 
Calvin 1 in their study of wheat gluten. The gluten was pre- 
pared by washing flour free of its starch with distilled water. 
It was rolled out between glass plates to uniform thickness, and 
small round pellets weighing approximately 1.25 gram were cut 
from this with a large cork borer. Gluten behaves very much 
like fibrin and gelatin. Thus, it swells more in any acid than 

Tred W. Upson and J. W. Calvin: Personal Communication (1914); 
Jour. Am. Chem. Soc, 37, 1295 (1915). 



130 



OEDEMA AND NEPHRITIS 



in pure water. This is well shown in Fig. 42. The beaker on 
the extreme left shows a pellet of gluten in distilled water. The 
six beakers to the right contain progressively stronger solutions 














, » — — — — - 






a 


~ , - . — 






> J 


Hi J 











Figure 42. 



of lactic acid ranging from n 500 to n 10. Entirety similar series 
may be arranged for other acids. 




Figure 43. 



The addition of any salt to an acid solution inhibits the 
swelling, and this the more the higher the concentration of the 
added salt. This is well illustrated in Figs. 43, 44 and 45. Beaker 1 




Figure 44. 



in each of the series contains pure n/100 lactic acid; the remain- 
ing beakers, increasingly greater amounts (from m/1000 to 
m/25) of different salts, potassium chlorid in Fig. 43, dipotassium 
phosphate in Fig. 44 and potassium tartrate in Fig. 45. 

Figs. 46 and 47 bring out these relationships yet more clearly. 



ABSORPTION, SECRETION— CELLS AND TISSUES 131 

In Fig. 47 is shown the amount of water absorbed in different 
concentrations of three different acids. Concentration is plotted 




Figure 45. 



on the horizontal, increase in weight in terms of the original 
weight of the (moist) pellet on the vertical. The optimal swelling 
point is exceeded earlier in the case of hydrochloric acid than 



2.0 - 




Figure 46. 

in the case of lactic or acetic. A highly interesting feature of 
these gluten experiments is the fact that even such " weak " 
acids as lactic and acetic show an optimal concentration for swell- 
ing beyond which the protein swells less than in lower concentra- 
tions of the acid. 



ABSORPTION, SECRETION— CELLS AND TISSUES 133 



Fig. 46, in addition to showing that all salts reduce the swell- 
ing of gluten in an acid solution, also shows that at the same con- 
centration different salts are unequally effective in this regard. 
Thus, calcium chlorid produces a greater dehydration than potas- 
sium chlorid, and the tartrate is more powerful than the phosphate. 

Some earlier experiments by T. B. Wood and W. B. Hardy 1 
on the " cohesiveness " of gluten bring out from an experimental 
point of view what amount in essence to the same facts as those 
of Upson and Calvin. Wood and Hardy found gluten to 
" disintegrate " and "dissolve" in dilute acids. The loss of 
cohesion depended upon the nature of the acid and its concen- 
tration and in about the way in which the swelling of fibrin, 
gelatin and gluten depends upon these factors. Salts inhibited 
the action of the acid, both their concentration and their nature 
being of great importance in the matter. 

These experiments show how plant protein behaves in a fash- 
ion identical with the previously studied animal proteins. Their 
importance in the general biological problem of water absorp- 
tion will become apparent as we proceed. The value of Wood, 
Hardy, Upson and Calvin's work in many other directions, 
as for the theory and practice of flour manufacture, bread mak- 
ing, etc., needs no emphasis. 2 

6. Observations on the Swelling of Aleuronat 

In order to obtain data upon the water-absorbing powers of 
another plant protein, the behavior of " natural " aleuronat grains 
was studied. 3 Aleuronat, as is well known, is not a single protein 
but a mixture of several. The results detailed in the following 

X T. B. Wood and W. B. Hardy: Proc. Roy. Soc, London, Series B, 81, 
38 (1908). 

2 See in this connection F. W. Upson and J. W. Calvin: Bull. Agric. Exp. 
Station of Nebraska, Research Bull. No. 8 (1916); also Wolfgang Ostwald: 
Kolloid-Zeitschr., 25, 26 (1919); H. Luers and Wolfgang Ostwald: ibid., 
25, 82 (1919). See also L. J. Henderson and E. J. Cohn: Jour. Biol. Chem., 
36, 581 (1918); L. J. Henderson: Jour. General Physiology, 1, 387 (1919); 
ibid., 1, 459 (1919). In these papers Cohn and Henderson accept as 
correct for the swelling of flour proteins all the laws, previously stated by 
me for the swelling of animal proteins in health and disease and the cor- 
rectness of which they have so often denied. 

3 Martin H. Fischer and Marian O. Hooker: Kolloid-Zeitschr., 26, 
49 (1920) ; these studies were ready for publication in 1916 since which time 
they were held by the British censor. 



134 



(EDEMA AND NEPHRITIS 



experiments are in consequence not to be interpreted as the effects 
of various external conditions upon a single protein, but rather as 
the sum of such effects upon several. Since living cells, however, 
also contain several proteins in mixture, the behavior of aleuronat 
is of significance for the analysis of living cells when subjected to 
similar conditions. 

The experiments were carried out by introducing weighed 
amounts (one gram) of air dry aleuronat into calibrated test tubes 
(19 mm. in diameter) containing a constant volume of liquid (40 
cc). The degree of swelling of the aleuronat was then expressed by 
measuring the height of the aleuronat columns in the different 
tubes, After introducing the aleuronat into the different solutions 
the contents of the tubes were thoroughly mixed by turning these 
about several times, care being taken to treat all in exactly the 
same fashion. Like most colloid reactions, the swelling of aleuro- 
nat takes time. Unless otherwise specified, measurements as given 
below refer to the values obtained in the different media at the 
end of eighteen hours. 

(a) Excepting in very low concentrations of acid, aleuronat 
swells more in such a medium than in distilled water. This is 
shown in Table LI. The figures in the columns should be read 
downwards as this is the order in which each series of experiments 
was done. With slight allowance for errors, due to uneven set- 
tling, etc., the columns may also, however, be read across. 

Table LI shows that in the case of the " strong" acids (hydro- 

TABLE LI 
Aleuronat — Acids 



Height of aleuronat column in mm. after 18 hours in 



Concentration of solution 


Hydro- 
chloric 


Nitric 


Sul- 
phuric 


Lactic 


Formic 


Tar- 
taric 


40 cc. 


H 2 (control) 


24 


25 


25 


25 


25 


25 


1 cc. 


n/10acid+39 cc. H2O 


22 


23 


23 


24 


22 


23 


2 cc. 


" +38 cc. " 


37 


23 


24 


34 


31 


25 


3 cc. 


" +37 cc. " 


44 


40 


26 


38 


37 


29 


4 cc. 


" +36 cc. " 


49 


42 


26 


41 


38 


33 


5 cc. 


" +35 cc. " 


48 


39 


26 


44 


39 


35 


1\ cc. 


" +32i cc. " 


45 


34 


25 


47 


43 


40 


10 cc. 


" +30 cc. " 


40 


29 


25 


48 


45 


44 


15 cc. 


" +25 cc. " 


34 


25 


25 


49 


45 


46 


20 cc. 


" +20 cc. " 


31 


25 


26 


53 


47 


48 


30 cc. 


" +10 cc. " 


28 


25 


26 


55 


50 


50 


40 cc.n/10 acid 


27 


25 


26 


55 


50 


50 



ABSORPTION, SECRETION— CELLS AND TISSUES 135 



chloric, nitric, sulphuric) there is with every increase in concen- 
tration an increase in swelling, but this continues only up to a cer- 
tain point beyond which a decreased swelling is noted. Figs. 




48 and 49, in which are reproduced photographically the results for 
hydrochloric and sulphuric acids, illustrate this behavior better 
than many words. In the case of the " weak " acids (lactic, 
formic, tartaric) there is, with progressive increase in concentra- 
tion, within the limits used in these experiments, only a pro- 



136 



(EDEMA AND NEPHRITIS 



gressive increase in swelling. Fig. 50 shows the appearance of the 
tubes when lactic acid is used. 

Table LI reaffirms the older findings which, while often empha- 
sized before, have not as yet received adequate consideration at 
the hands of critics who, in working on the problems of acid intoxi- 
cation in living organisms, remain ignorant of these simple facts 
regarding the effects of acids upon ordinary proteins. The table 
again shows that the degree of swelling is nowhere proportional to 
the hydrogen ion concentration alone. Sulphuric acid, for 




Figure 49. 



example, which in these dilute solutions yields, on dissociation, 
about the same number of hydrogen ions as nitric or hydrochloric 
acid produces little more swelling than distilled water. On the 
other hand, the weakly dissociated lactic, formic and tartaric 
acids are, in the production of swelling almost as powerful as 
hydrochloric. As the end members of these series show, there 
exist concentrations of such " weak " organic acids capable of 
producing an even greater swelling of aleuronat than is pro- 
duced by the optimal concentrations of hydrochloric or nitric 
acids. 

Table LI shows that in the lowermost acid concentration there 
is even less swelling of the aleuronat than in pure water. This 



ABSORPTION, SECRETION— CELLS AND TISSUES 137 



effect of very low concentrations of acid in producing a slight 
decrease in the swelling of aleuronat is brought out in greater 
detail in Table LII. 

TABLE LII 



Aleuronat — Acids 







Height of aleuronat column in mm. 






after 18 h 


ours in 


Concentration of solution 










Hydrochloric 


Nitric 


40 cc. H 2 (control) 


24 


24 


0.1 cc. 


n/10 acid +39. 9 cc. H 2 


24 


24 


0.2 cc. 


" +39.8 cc. " 


23 


24 


0.3 cc. 


" +39.7 cc. " 


22 


24 


0.4 cc. 


" +39.6 cc. " 


23 


24 


0.5 cc. 


" +39.5 cc. " 


23 


24 


0.75 cc. 


" +39.25 cc. " 


23 


22 


1. cc. 


." +39. cc. " 


23 


21 


2. cc. 


" +38. cc. " 


36 


30 


3. cc. 


" +37. cc. 4 * 


42 


35 


4. cc. 


" +36. cc. " 


46 


38 


5. cc. 


" " +35. cc. " 


46 


38 




Figure 50. 



(b) 
water. 



The swelling of aleuronat is greater in alkalies than in pure 
This is illustrated for sodium hydroxid in Table LI 1 1 and 



138 



(EDEMA AND NEPHRITIS 



Fig. 51. The amount of swelling at first rises with progressive 
increase in the concentration of the alkali until an optimum is 



TABLE LIII 

Aleuronat — Sodium Hydroxid 



Concentration of solution 


Height of aleuronat column 
in mm. after 18 hours 


40 cc. H 2 (control) 






24 


1 cc. 


n/10 NaOH+39 


cc. H2O 


22 


2 cc. 




+38 


cc. " 


32 


3 cc. 




+37 


cc. " 


32 


4 cc. 




+36 


cc. " 


34 


5 cc. 




+35 


cc. " 


36 


7.5 cc. 




+32 


5 cc. " 


41 


10 cc. 




+30 


cc. " 


38 


15 cc. 




+25 


cc. " 


33 


20 cc. 




+20 


cc. " 


30 


30 cc. 




+10 


cc. " 


25 


40 cc. 


n/10 NaOH 






23 




Figure 51. 



reached, beyond which further addition of alkali brings about a 
diminished swelling. In very low concentrations of alkali the 
amount of swelling may actually be slightly less than in pure water, 
as apparent in the second tube from the left in Fig. 51 and as 
illustrated in greater detail in Table LIV. 

(c) As previously noted for other proteins, the addition of 



ABSORPTION, SECRETION— CELLS AND TISSUES 139 



TABLE LIV 

Aleuronat — Sodium Hydroxid 



Concentration of solution 



Height of aleuronat column 
in mm. after 18 hours 



40 cc. H 2 (control) 
0.1 cc. n/10 NaOH+39.9 cc. H2O 



0.2 cc. 
0.3 cc. 
0.4 cc. 
0.5 cc. 
0.6 cc. 
0.8 cc. 
1.0 cc. 
1.5 cc. 
2.0 cc. 
3.0 cc. 



+39.8 cc. 
+39.7 cc. 
+39.6 cc. 
+39 . 5 cc. 
+39.4 cc. 
+39.2 cc. 
+39.0 cc. 
+38.5 cc. 
+38.0 cc. 
+37.0 cc. 



24 
25 
25 
25 
24 
24 
24 
23 
23 
26 
32 
40 



various salts reduces the amount of swelling induced in aleuronat 
by any acid or alkali. Table LV and Fig. 52 reproduce the find- 
ings obtained when sodium chlorid is added in increasing concen- 
tration to hydrochloric acid, while Tables LVI and LVII with the 
corresponding Figs. 53 and 54 show the results when sodium 
chlorid and sodium sulphate are added, respectively, to sodium 
hydroxid. In all instances there is a progressive decrease in 
amount of swelling as the concentration of the added salt rises. 

TABLE LV 



Aleuronat — Acid + Sodium Chlorid 



Concentration of solution 


Height of aleuronat column 
in mm. after 18 hours 


40 cc. H 2 (control) 






24 


5 cc. n/10 HC1+36.0 cc. H 2 




44 


5 cc. 


n/10 HC1 +0.1 cc. 


m/1 NaCl+35.9 


cc. H2O 


38 


5 cc. 


" +0.2 cc. 


" +35.8 


cc " 


37 


5 cc. 


" +0.3 cc. 


" +35.7 


cc. " 


34 


5 cc. 


" +0.4 cc. 


" +35.6 


cc. " 


32 


5 cc. 


" +0.5 cc. 


" +35.5 


cc. " 


31 


5 cc. 


" +0.75 cc. 


" +35.25 cc. " 


29 


5 cc. 


" +1.0 cc. 


" +35.0 


cc. " 


27 


5 cc. 


" +1.25 cc. 


" +34.75 cc. " 


26 


5 cc. 


" +1.5 cc. 


" +34.5 


cc. " 


28 


5 cc. 


" +2.0 cc' 


" +34.0 


cc. " 


28 



(d) While all salts decrease the swelling of aleuronat in the 
presence of an acid or an alkali certain salts are more powerful in 
this regard than are others. The comparative effects of a series 
of potassium salts upon swelling in hydrochloric acid are shown in 



140 



(EDEMA AND NEPHRITIS 




TABLE LVI 

Aleueonat — A Ikali + Sodium Chlorid 



Concentration of solution 


Height of aleuronat column 
in mm. after 18 hours 


40 cc. 


H 2 (control) 








25 


5 cc. n/10 NaOH+36 cc. H 2 








36 


5 cc. n/10 NaOH +0 . 1 cc. m/1 NaCl +35 


9 


cc. H2O 


35 


5 cc. 


" +0.2 cc. " 


" +35 


8 


cc. " 


35 


5 cc. 


" +0.3 cc. 44 


" +35 


7 


cc. 44 


34 


5 cc. 


" +0.4 cc. " 


" +35 


6 


cc. 44 


34 


5 cc. 


+0.5 cc. " 


" +35 


5 


cc. 44 


34 


5 cc. 


" +0.75 cc. 44 


" +35 


25 


cc. 44 


35 


5 cc. 


44 +1.0 cc. " 


" +35 





cc. 44 


34 


5 cc. 


+1.25 cc. " 


" +34 


75 


cc. 44 


33 


5 cc. 


" +1.5 cc. 44 


" +34 


5 


cc. 44 


34 


5 cc. 


" +2.0 cc. " 


44 +34 





cc. 44 


33 



ABSORPTION, SECRETION— CELLS AND TISSUES 141 




Figure 54. 



Table LVIII and Fig. 55; the effects of the same series upon 
swelling in sodium hydroxid are shown in Table LIX. While 
in the first instance the order, when that least powerful is 
given first, is: chlorid, bromid, nitrate, iodid, acetate, sulpho- 



142 



(EDEMA AND NEPHRITIS 



TABLE LVII 

Aleuronat — Alkali + Sodium Sulphate 



Concentration of solution 


Height of aleuronat column 
in mm. after 18 hours 


40 cc. H2O (control) 






25 


4 cc. n 


10 NaOH +36 cc. H 2 






42 


4 cc. n, 


'10 NaOH +0.1 cc. m l Ns 


12SO4 + 35.9 


cc. H2O 


00 
00 


4 cc. 


+0.2 cc. " 


+35.8 


cc. " 


36 


4 cc. 


" +0.3 cc. " 


" +35.7 


cc. \ 


35 


4 cc. 


+0.4 cc. " 


+35.6 


cc. " 


33 


4 cc. 


' " +0.5 cc. " 


+35.5 


cc. " 


32 


4 cc. 


" +0.75 cc. " 


+35.25 


cc. " 


29 


4 cc. 


" +1.0 cc. " 


+35.0 


cc. " 


29 


4 cc. 


" +1.25 cc. " 


+34.75 cc. " 


28 


4 cc. 


+1.5 cc. " 


+34.5 cc. 


28 


4 cc. 


+2.0 cc. " 


+34.0 


cc. " 


27 



TABLE LVIII 

Aleuronat — Acid -{-Potassium Salts 



Concentration of solution 


Height of aleuronat 
column in mm. after 
18 hours 


40 cc. H2O (control) 






25 


4 cc. n/10 HC1+36 cc. H2O 






51 


4 cc. n 10 HCl+0.1 cc. m/1 K chlorid 


+35.9 cc. H2O 


46 


4 cc. 


" +0.1 cc. " 


K bromid 


+35.9 cc. " 


46 


4 cc. 


" +0.1 cc. " 


K nitrate 


+35.9 cc. " 


45 


4 cc. " 


" +0.1 cc. " 


K iodid 


+35.9 cc. " 


43 


4 cc. 


" +0.1 cc. " 


K acetate 


+35.9 cc. " 


42 


4 cc. " 


" +0.1 cc. " 


K sulphocyanate+35.9 cc. " 


41 


4 cc. " 


" +0.1 cc. " 


K tartrate 


+35.9 cc. " 


38 


4 cc. " 


" +0.1 cc. " 


K citrate 


+35.9 cc. " 


23 




Figure 55. 



ABSORPTION, SECRETION— CELLS AND TISSUES 143 



cyanate, tartrate, citrate, this order is practically reversed in the 
second. 



TABLE 


LIX 




Aleuronat — Alkali -{-Potassium Salts 








Height of aleuronat 


Concentration of solution 




column in mm. after 






18 hours 


40 cc. H2O (control) 




25 


4 cc. n/10 NaOH +36 cc. H 2 




37 


4 cc. n/10 NaOH +0.1 cc. m/1 K citrate 


+35.9 cc. H2O 


36 


4 cc. " " +0.1 cc. " K tartrate 


+35.9 cc. " 


36 


4 cc. * " +0.1 cc. " K acetate 


+35.9 cc. " 


35 


4 cc. " " +0.1 cc. " K bromid 


+35.9 cc. " 


35 


4 cc. " " +0.1 cc. " K nitrate 


+35.9 cc. " 


34 


4 cc. " " +0.1 cc. " K sulphocyanate +35.9 cc. " 


34 


4 cc. " " +0.1 cc. " K iodid 


+35.9 cc. " 


31 


4 cc. " " +0.1 cc. " K chlorid 


+35.9 cc. " 


31 



TABLE LX 
Aleuronat — Acid +Chlorids 









Height of aleuronat 




Concentration of solution 




column in mm. after 
18 hours 


40 cc. 


H2O (control) 




24 


4 cc. 


n/10 HC1+36 cc. H2O 




53 


4 cc. 


n/10 HC1+0. 1 cc. m/1 iron (ic) +35 


9 cc. H2O 


57 


4 cc. 


" +0.1 cc. " aluminium +35 


9 cc. " 


52 


4 cc. 


" " +0.1 cc. " ammonium +35 


9 cc. " 


49 


4 cc. 


" " +0.1 cc. " sodium +35 


9 cc. " 


47 


4 cc. 


" " +0.1 cc. " copper (ic) +35 


9 cc. " 


47 


4 cc. 


" " +0.1 cc. " magnesium +35 


9 cc. " 


46 


4 cc. 


" +0.1 cc. " calcium +35 


9 cc. " 


45 


4 cc. 


" +0.1 cc. " strontium +35 


9 cc. " 


44 



TABLE LXI 

Aleuronat — A Ikali + Chlorids 



Concentration of solution 


Height of aleuronat 
column in mm. after 
18 hours 


40 cc. 


H2O (control) 






25 


4 cc. n/10 NaOH 






37 


4 cc. n/10 NaOH +0.1 cc. 


m/1 NaCl +35 


9 cc. F?0 


36 


4 cc. 


" +0.1 cc. 


" NH4C1+35 


9 cc. " 


35 


4 cc. 


" +0.1 cc. 


" FeCls +35 


9 cc. " 


33 


4 cc. 


" +0.1 cc. 


" SrCl 2 +35 


9 cc. " 


32 


4 cc. 


" +0.1 cc. 


" CaCb +35 


9 cc. " 


29 


4 cc. 


" +0.1 cc. 


" MgCl 2 +35 


9 cc. " 


27 


4 cc. 


" +0.1 cc. 


" AlCIs +35 


9 cc. " 


27 


4 cc. 


" +0.1 cc. 


" CuCl 2 +35 


9 cc. " 


26 



144 



(EDEMA AND NEPHRITIS 



The effects of salts with a common acid radical but different 
basic ones in reducing, at a given concentration, the swelling of 
aleuronat in the presence of an acid or an alkali are shown in 
Tables LX and LXI. All these salts reduce swelling with the 
exception of those in the acid series which hydrolyze strongly 
and thus tend to yield an overplus of acid. The order in 




Figure 56. 



which the different basic radicals prove effective may be seen in 
the tables. 

(e) At an " osmotic " concentration about equal to that in 
which the different salts greatly reduce the swelling of aleuronat 
in the presence of an acid or alkali, different non-electrolytes are 
practically without effect. Tables LXII and LXIII and Fig. 56 
illustrating the acid series show this. The swelling in the presence 
of urea, or the two alcohols or the two sugars is not measurably 
different from that in the pure acid. 



ABSORPTION, SECRETION— CELLS AND TISSUES 145 
TABLE LXII 



Aleuronat — Acid -{-Non-Electrolytes 



Concentration of solution 


Height of aleuronat 
column in mm. after 
18 hours 


40 cc. H2O (control) 
4 cc. n/10 HCl+36 cc. H 2 

4 cc. n/10 HCl+0.1 cc. 2 m. urea +35.9 cc. H2O 
4 cc. " " +0.1 cc. " methyl alcohol +35.9 cc. " 
4 cc. " " +0.1 cc. '* ethyl alcohol +35.9 cc. " 
4 cc ** *' — \~ 1 cc 14 dextrose - \~ 35 9 cc " 
4 cc. " " +0.1 cc. " saccharose +35.9 cc. " 


25 
48 
48 
48 
48 
49 
49 


TABLE LXIII 




Aleuronat — Alkali + Non-Electrolytes 




Concentration of solution 


Height of aleuronat 
column in mm. after 
18 hours 


40 cc. H2O (control) 
4 cc. n/10 NaOH+36 cc. K2O 

4 cc. n/10 NaOH+0.1 cc. 2 m. urea +35.9 cc. H 2 
4 cc. " " +0.1 cc. " methyl alcohol +35.9 cc. " 
4 cc. " " +0.1 cc. " ethyl alcohol +35.9 cc. " 
4 cc. " " +0.1 cc. " dextrose +35.9 cc. " 
4 cc. " " +0.1 cc. " saccharose +35.9 cc. " 


25 
38 
38 
38 
38 
36 
38 


6. Hydration and Dehydration in Liquid Colloids 



The three colloids discussed thus far are essentially solid in 
character, and their behavior corresponds, as we shall see imme- 
diately, with the more solid constituents of living matter such 
as the muscles, parenchymatous organs, nervous tissues or eyes 
of our own bodies. But permeating these more solid structures 
we find in the higher animals streams of liquid colloid material 
which we call blood, lymph or tissue juice. How do such liquid 
protein colloids behave when subjected to the action of acids, 
alkalies and salts? Do they " swell " and " shrink " as do the 
solid colloids already discussed? The answer to this question, 
which is of fundamental importance for the solution of a whole 
series of biological phenomena, has been given us through 
the work, more especially of Franz Hofmeister, 1 , Wolfgang 

1 Franz Hofmeister: Arch. f. exp. Path. u. Pharm., 27, 395 (1890); 
ibid., 28, 210 (1891). 



146 



(EDEMA AND NEPHRITIS 



Pauli, 1 W.B.Hardy, 2 P. von Schroeder, 3 Hans Handovsky 4 and 
K. Schorr. 5 A liquid colloid such as a solution of gelatin, blood 
serum or egg albumin cannot, of course, be seen to swell or shrink 
in a test-tube. We must therefore use some other method of 
discovering such changes and measuring them. This is accom- 
plished by determining the viscosity of the liquid colloid by 
permitting it to flow through a capillary tube. Evidently, as. 
the separate colloid particles in a colloid solution swell, they 
take up the pure solvent about them, and as such swelling pro- 
gresses it must become increasingly difficult for the particles 
to move over each other. The viscosity of the solution must 
therefore rise, and this betrays itself by an increase in the time 
required for a certain volume of the colloid solution to flow through 
a standard capillary tube. Conversely, as the particles shrink 
the pure solvent is squeezed off, and so the viscosity must tend 
to fall back toward that of the pure solvent. 

Wolfgang Pauli 6 has in this way studied blood serum from 
which the various admixed crystalloids have been removed by 
long dialysis against pure water. Such a solution is perfectly 
clear and stable. If its viscosity is measured it is found to be 
considerably higher than that of pure water owing to the colloid 
material in it. If a trace of acid is added the viscosity is enor- 
mously increased. But with progressive additions an upper 
limit is reached in the case of such acids as hydrochloric, hydro- 
bromic, nitric or sulphuric, beyond which a further addition of 
acid does not further increase, but decreases viscosity. For the 
weaker organic acids, such as acetic, no such optimal point has 

1 Wolfgang Pauli: Pfluger's Arch., 67, 219 (1897); ibid., 71, 1 (1898); 
Hofmeister's Beit. z. chem. Physiologie, numerous papers in the years 1902 
to 1908; Biochem. Zeitschr., 17, 235 (1909); ibid., 18, 340 (1909); ibid., 24, 
239 (1910). A general statement of his views is found in Kolloid-Zeitschr., 
7, 241 (1910). 

2 W. B. Hardy: Jour. Physiol., 24, 288 (1899); ibid., 33, 251 (1905); 
Proc. Royal Soc. London, Series B, 79, 413 (1907); Zeitschr. f. physik. Chem., 
33, 385 (1900). 

3 P. von Schroeder: Zeitschr. f. physik. Chem., 45, 75 (1903). 

4 Hans Handovsky: Fortschritte in der Kolloidchemie der Eiweiss- 
korper, Dresden (1911), where references to his earlier papers will be found. 

6 K. Schorr: Cited by Pauli and Handovsky. 

6 Wolfgang Pauli: Naturwissensch. Rundschau, 21, 3 (1906); Physical 
Chemistry in the Service of Medicine, 136, translated by M. H. Fischer, 
New York (1907). Pauli and H. Hando sky: Biochem. Zeitschr., 18, 340 
(1909). 



ABSORPTION, SECRETION— CELLS AND TISSUES 147 



yet been found. The addition of any salt to the acidified serum 
markedly reduces the viscosity. With the same salt the degree 
of reduction increases with the concentration of the salt. With a 
given concentration of any series of salts very different degrees 
of reduction in viscosity are obtained. Thus, when sodium 
salts are compared, the chlorid, nitrate and sulphocyanate are 
found to be less powerful than the acetate or sulphate, and in 
the order named. The addition of a non-electrolyte is con- 
spicuously less effective in this regard. A practically identical 
series of findings has been established for the effects of alkali 
or of alkali plus various salts or non-electrolytes. 

It is readily apparent that these statements are point for 
point analogous to those made previously regarding fibrin, gelatin 
and gluten, and hence justify the conclusion that liquid (protein) 
colloids behave toward various external conditions in the same way 
as do the more solid ones. 

These changes in the swelling of fibrin, gelatin or gluten, 
or the viscosity changes of a liquid colloid, may opportunely 
be correlated here with changes in certain other properties. 
When acids, bases or salts are added to a protein colloid we ob- 
serve variations not only in its swelling or viscosity, but in its 
precipitability or coagulability and in its optical behavior. What 
relation do these bear to each other? The fundamental change 
remains the same, namely, a change in the hydration capacity 
of the involved colloids. As already pointed out, whatever makes 
gelatin or fibrin swell increases viscosity, and vice versa. As the 
degree of hydration is increased, the intimacy of the colloid 
with its solvent is evidently increased, and so we should expect 
its stability to be increased. We are not surprised, therefore, 
to find that whatever increases hydration increases the stability 
of a colloid, while, conversely, whatever does the reverse favors 
instability, in other words, precipitation and coagulation. Thus, 
pure serum albumin is easily precipitated by heat or alcohol. 
When a little acid is added the hydration capacity of the colloid is 
increased and corresponding herewith, its precipitability through 
heat or alcohol is lost. But if yet more acid is added the 
hydration optimum is exceeded and now heat and alcohol regain 
their power of precipitating the protein. In a similar way the 
protein after being rendered non-precipitable through acid can 
again be precipitated by heat if a salt is added to the acid pro- 



148 



(EDEMA AND NEPHRITIS 



tein, for this again lowers the hydration capacity of the col- 
loid. 1 

An analogous series of observations is available regarding 
changes in the optical behavior of protein colloids. We see from 
this that a series of reactions in certain protein colloids which at 
first seem to have nothing to do with each other are reducible in 
the end to a comparatively simple set of changes. And as we 
proceed we shall find that protoplasm, which is in essence but a 
colloid matrix of the type of fibrin, gelatin or blood serum, fol- 
lows similarly simple laws. In the normal water content of a 
cell we shall see again a swollen colloid, and in oedema the same 
colloid swollen to a greater • amount. Changes in the viscosity 
of the blood will come to mean changes in its degree of hydration, 
while corneal opacities in glaucoma and changes in the normal 
refraction and diffraction of the clear media will come to mean 
dehydration and precipitation of certain protein colloids present 
in the tissues of the eye. 



7. On the Nature of the Increased and Decreased Hydration 
Capacity of the Proteins 

While the theory of the increases and decreases in the water 
holding powers of the proteins is of no importance for the argu- 
ment which follows, brief reference to its probable nature here 2 
may serve to hold together in more easily grasped form the large 
number of isolated facts thus far detailed. Without referring to 
the theories advanced by other workers in this field (large por- 
tions of which are undoubtedly correct for certain aspects of the 
colloid chemistry of the proteins) our own opinion somewhat dog- 
matically framed may be thus expressed. 

The pure proteins (as polymerized amino-acids) are the analogs 

1 The ordinary heat coagulation test for albumin in the urine makes use 
of these principles. The albumin is coagulated best when acid and salt are 
first added to the urine. 

2 For details and references to the literature see Martin H. Fischer, 
Marian O. Hooker, and George D. McLaughlin: Science, 48, 143 (1918); 
ibid., 49, 615 (1919): Chem. Engineer, 27, 155, 184, 223, 253, 271 (1919); 
Jour. Lab. and Clin. Med., 5, 207 (1920); ibid., 5, 352 (1920); a running 
account is found in Martin H. Fischer: Soaps and Proteins, New York 
(1920), in press. 



ABSORPTION, SECRETION— CELLS AND TISSUES 149 



of the fatty acids. If we write the elementary constitution of a 
fatty acid as : 

z-COOH 

then that of an amino- (fatty) acid may be written: 

z-COOH 



the x standing for any nucleus we please. How now (remembering 
the fundamentals of the nature of the hydrophilic colloid state 
developed earlier l ) do these act as solvents for water? Generally 
speaking, very poorly. The ordinary fatty acids (like oleic, lauric, 
palmitic, stearic) are generally said to take up no water at all 
(or, in our terminology, they do not " swell ") and the same is 
largely true of the polymerized amino-acids which we call protein. 
Casein, for example, sinks as a non-sticky, white powder to the 
bottom of a vessel of water; fibrin and gelatin do absorb some 
water as evidenced in the experiments described above. 

As soon, however, as an alkali is added to a fatty acid, soap is 
formed which, as a new compound, is also a better solvent for the 
water. Were we ignorant of the chemical union that had taken 
place we would say that " the hydration capacity of the fatty 
acid had been increased " through the addition of the alkali. 
Actually the fatty acid has been replaced by soap and the " in- 
creased swelling " is due to the better solvent properties of the 
latter for water. Things are identical if protein replaces the pure 
fatty acid. A " soap " is again formed and hence the greater 
swelling of casein, fibrin, gelatin, gluten or aleuronat when an 
alkali is added to them. 

The power for thus taking up water varies, however, with the 
type of base introduced into a given fatty acid (in other words 
with the kind of soap formed), and in about the following order 
when the base yielding the highest hydration capacity is given 
first* 

NH 4 , K, Na, Li, Mg, Ca, Ba (.?), Pb, Fe, Hg. 

It will be remembered that this is also the order in which different 
hydroxids (irrespective of their dissociation values and hydroxyl 
ion concentrations) affect the swelling of various proteins. 

1 See page 50. 



150 



OEDEMA AND NEPHRITIS 



There exists, however, an interesting chemical difference 
between the fatty acids and the amino- (fatty) acids which we call 
proteins. This is expressed in the possession by the latter of the 
NH2 group. While the former are purely " acid " in character, 
the latter are not only acid but alkaline as well, or, as commonly 
expressed, amphoteric. While the fatty acids can be treated only 
with an alkali to yield new compounds, the amino- (fatty) acids 
can be treated not only with this but with an acid as well. Against 
the one series of compounds yielded by the fatty acids we can 
produce at least two in the case of the amino-acids. Depending 
upon the acid used we can make the chlorids, bromids, iodids, 
sulphates, tartrates and citrates out of " neutral " casein, fibrin, 
gelatin, gluten or aleuronat. These substances (salts) again have 
a higher hydration capacity than the pure proteins, and hence the 
reason why all acids added to any pure protein increase its hydra- 
tion capacity. But these hydration capacities again differ with 
the different acid radicals, and hence the statement that hydro- 
chloric acid is a more powerful swelling agent than acetic, this than 
sulphuric, etc. 

How now may we understand the hydrating effects of neutral 
compounds, like sodium chlorid, upon substances like gelatin or 
fibrin and the lack of such effects when magnesium chlorid or 
sulphate is used? Compounds are again formed (after the hydroly- 
sis of the salts in the water) yielding in the first instance sodium- 
protein-chlorid, in the second magnesium-protein-chlorid or mag- 
nesium-protein-sulphate. The first is a better solvent for water 
than the pure protein; the second an even worse one. 

The action of substances like urea, pyridin and the amins is 
somewhat more complicated but the formation of new compounds 
with different solvent capacities for water is again a fundamental 
factor. These compounds are not, however, of the simple type 
resulting when (acids or) alkalies are used, as already apparent 
from the fact that the addition of acid or neutral salt does not 
reduce their swelling as anticipated, while sugars do this in a 
degree unexpected in simple (acid or) alkali proteinates. 

How now may be understood the effects of the addition of any 
neutral salt to an acid or alkali proteinate? First to be con- 
sidered is the chemical possibility of replacing the acid or base of 
the proteinate by one of the radicals of the added salt. To replace 
a sodium radical by potassium or an acetate radical by a chlorid is 



ABSORPTION, SECRETION— CELLS AND TISSUES 151 

to increase the swelling capacity ; to replace them by magnesium or 
a sulphate radical is to decrease the swelling capacity. But 
where such chemical interchange is out of the question, as when 
sodium chlorid is seen to reduce the swelling of an alkalinized 
protein (sodium proteinate) what is it that happens then? The 
salt affects the solvent, namely, water. The neutral salt combines 
with water, as first insisted upon by Franz Hofmeister, and the 
protein mass is deprived of its " solvent " by this amount. Or, 
put in another way, the protein compound is a poorer solvent for 
salt-water than for pure water. 

It must be remembered, finally, that these remarks cover only 
one aspect of the colloid behavior of systems in which protein 
appears, albeit the most important one for the normal physiology 
of protoplasm. This, as we shall see, is essentially nothing but a 
solution of water in protoplasmic material. Another aspect of 
the whole problem, namely, that of the solubility of protein in 
water, is returned to later. 1 

Ill 

THE ANALOGY BETWEEN THE SWELLING OF CERTAIN 
PROTEIN COLLOIDS AND THE SWELLING OF PROTO- 
„ PLASM 

Having become familiar with the effect of various external 
conditions on the swelling of several simple so-called hydro- 
philic colloids (fibrin, geiatin, gluten, aleuronat, blood serum), 
we have at our disposal some facts which we may utilize in an 
attempt to analyze the ways and means by which tissues hold 
their normal amount of water, and to discover how under altered 
external conditions they may come to hold more or less than is 
considered normal. It is evident that could we show that the 
same conditions which make fibrin, gelatin or gluten take up and 
give off water, affect protoplasm similarly, a real step forward 
in the solution of this problem of the absorption and secretion 
of water by the tissues would be made. This can be done and 
with great simplicity. As the following paragraphs show, the 
absorption of water by various tissues is entirely analogous to 
the absorption of water by fibrin, gelatin, gluten or aleuronat. 



1 See page 509. 



152 



(EDEMA AND NEPHRITIS 



1. The Analogy between the Absorption of Water by Certain 
Protein Colloids and by Muscle 

Simple facts regarding the absorption of water by various 
cells and tissues are very numerous and date back to the earliest 
periods of modern physiology. We shall have occasion to review 
them later. So far as water absorption by muscle is concerned, 
0. Nasse 1 studied this question from an osmotic standpoint 
as far back as 1869, and E. Brucke 2 touched some aspects of 
the problem even earlier. Most of the investigations of this 
particular type of tissue made since then are useless for our 
purposes because they antedate the years in which adequate 
use of the principles of physical chemistry first began to be 
made in biological studies. The period of interest to us begins 
with 1898, when Jacques Loeb 3 published the results of some 
experiments on the influence of acids, alkalies and various salts 
on the absorption of water by the gastrocnemius muscle of the 
frog. He found that muscle absorbs much water if placed in 
distilled water or in solutions of various acids or alkalies. 
From his earlier experiments he concluded that a muscle does 
not change in weight if kept in a solution having an osmotic 
pressure equal to that of the blood, but that it gains or loses 
weight if placed in solutions having respectively a lower or a 
higher osmotic pressure. About the same conclusion had been 
previously reached by Nasse. But Nasse noted that certain 
salts, notably the sulphates, bromids and iodids, exhibited 
a greater than calculated " osmotic " effect. Loeb made a 
similar observation when he discovered that in spite of isos- 
moticity a frog's muscle will absorb more water from a potas- 
sium chlorid solution than from one of sodium chlorid, and more 
from this than from one of calcium chlorid. The analogy be- 
tween the latter fact and the absorption of water by potassium, 
sodium and calcium soaps was pointed out, but our conceptions 
of the colloids had not at that time advanced to the point of 
recognizing in the soaps examples of this class of bodies. As 
much controversy has hedged about the question of the historical 

1 O. Nasse: Pfliiger's Arch., 2, 97 (1869). 

2 E. Brucke: Sitzungsber. d. math. Naturw. CI. d. kais. Akad. d. Wis- 
sensch., 55, 622 (1867). 

3 Jacques Loeb: Pfliiger's Arch., 69, 1 (1898): ibid., 71, 457 (1899); 
bid., 75, 303 (1899). 



ABSORPTION, SECRETION— CELLS AND TISSUES 153 



development of the colloid chemical theory of water absorption 
by protoplasm it is well to emphasize that Loeb not only never 
contributed anything to its establishment, but actually thrust 
such aside. 1 The action of acids and alkalies on muscle Loeb 
brought into harmony with the then current osmotic conceptions 
of absorption by assuming that they induced changes within the 
muscle tissues whereby the osmotic pressure of the cell contents 
was raised, as previously emphasized for a series of other animal 
tissues by H. J. Hambueger, 2 C. von Limbeck, 3 Gurber 4 and 
C. Eijkman. 5 

The experiments of Ralph W. Webster 6 and E. Overton 7 
followed those of Loeb. Webster concluded that osmotic 
effects could only explain the absorption from water and solu- 
tions of cane sugar. His careful study of the effects of electrolytes 
showed unequivocally that simple osmotic effects are out of the 
question here. Overton came to essentially the same conclusion 
and attempted to help out the problem by his conception of 
lipoid membranes about living cells and their entire impermea- 
bility to salts. He showed conclusively that Loeb's explanation 
of the action of acids and alkalies cannot be correct, for were 

^oeb: Pfiiiger's Arch., 77, 305 (1890) says: "The analogy between the 
absorption of water by soaps and by m iscle is of importance in explaining 
the mechanism of water-absorption. The majority of authors, for example, 
Hofmeister, assume that in the absorption of fluids by tissues we deal 
with imbibition; that is to say, with capillary phenomena. But in the 
absorption of fluid by soaps we deal with solution phenomena. The forces 
active here are osmotic and not the surface tension forces active in capillary 
phenomena." (In Bezug auf die Mechanik der Fliissigkeitsresorption ist 
die Analogie zwischen dem Verhalten von Seifen und dem Muckel von Be- 
deutung. Die Mehrzahl der Autoren, z. B. Hofmeister, nehmen an dass 
es sich bei der Resorption von Flussigkeiten in Geweben um Imbibition 
handle, d. h. um Capillaritatserscheinungen. Bei der Fliissigkeitsaufnahme 
in Seifen handelt es sich aber un Losungsvorgange. Die dabei maasgebenden 
Krafte sind osmotische Drucke und nicht die bei capillaren Vorgangen 
maasgebenden Oberflachenspannungen .) 

2 H. J. Hamburger: Arch. f. (Anat. u.) Physiol., 513 (1892); ibid., 153 
(1893); Zeitschr. f. Biol., 35, 252 and 280 (1897), where references to his 
earlier papers are found. See also Arch. f. (Anat. u.) Physiol., 31 (1898). 

3 C. von Limbeck: Arch f. exp. Path. u. Pharm., 35, 309 (1894). 

4 Gurber: Sitzberich. d. med. phys. Gesellsch., Wurzburg, Feb. 25 (1895). 
5 C. Eijkman: Virchow's Arch. f. path. Anat., 143, 448 (1896), where 

references to his earlier papers will be found. 

6 Ralph W. Webster: University of Chicago Decennial Publications, 10 
(1900); cited from a reprint. 

7 E. Overton: Pfiiiger's Arch., 92, 115 (1902). 



154 



(EDEMA AND NEPHRITIS 



all the proteins, carbohydrates and fats contained in muscle, 
split into their simplest digestion products they would still not 
yield a sufficient number of molecules to account, through con- 
ceptions of osmotic pressure, for the amount of water absorbed 
by muscle in the solution of an acid or an alkali. To certain 
other of Overton's ideas we shall have occasion to return later. 

Both in individual experimental results and in the conclusions 
drawn from them there exist many contradictions between the 
findings of these various authors. It is needless to touch upon 
them in detail. For a majority of these differences an explanation 
can readily be found. None of the authors mentioned ever studied 
the curves of absorption of water by muscle under various condi- 
tions. They weighed their muscles at arbitrary intervals of time, 
and drew their conclusions from these weighings — at times only 
one weighing. A moment's study of a few of the curves which 
accompany these paragraphs will show how wrong this is. (See 
Figs. 61 to 63.) To cite but one example, a muscle kept in any 
salt solution need not, and, in fact, usually does not, show a 
progressive increase or decrease in weight. It may at first show 
a very decided decrease and later an equally decided increase; 
or the reverse may be the case. If this fact is borne in mind, 
many of the statements made by these authors and not in har- 
mony with each other or with my own experimental results will 
find a ready explanation. 

We shall turn now to the conclusions to which I have been led 
from my own experiments, and see if in them we may not find 
an acceptable explanation of the apparently unattached and 
not easily accounted for facts observed by the previous workers 
in this field. My experiments were made with the hind legs 
of tree toads (Hyla) from which the skin had been removed, and 
with the gastrocnemius muscles of the frog (Rana) . The muscle 
preparations were carefully dried, weighed and placed in various 
solutions contained in lightly covered finger bowls. At various 
intervals they were removed from the solutions, carefully dried 
with filter paper, and weighed, and the amount of water they had 
lost or gained was calculated in per cent of the original weight 
of the muscle. From many such experiments the following 
conclusions of importance to the subject in hand were drawn. 
The conclusions are again lettered so as to permit ready com- 
parison with similarly lettered and corresponding conclusions 



ABSORPTION, SECRETION— CELLS AND TISSUES 155 



reached in the study of the absorption of water by fibrin, gelatin, 
gluten and aleuronat. 

(a) A muscle swells more in the solution of any acid than it 
does in pure water, but the amount of this swelling is greater 
in some acids than in others. Muscle swells most in a hydro- 
chloric acid solution, almost as much in a nitric acid solution 
of the same concentration, and less in acetic and sulphuric acids 
in the order named. Fig. 57 may serve as an illustration of this 

140 1 1 1 1 1 1 1 1 , 




Figure 57. 



fact. The experiments upon which these curves are based were 
made with the hind legs of tree toads (Hyla) from which the 
skin had been removed. 1 

An important relationship exists between the concentration 
of the acid employed and the amount that the muscle swells. 
This is readily apparent in Fig. 58 and Table LXIV, which con- 
tains the experimental findings from which the curves were 
constructed. In this series of experiments the gastrocnemius 
muscles of frogs (Rana) were used. There is first to be noted 
1 Martin H. Fischer; Pfluger's Arch., 124, 69 (1908). 



156 



(EDEMA AND NEPHRITIS 



an increase in the swelling with every increase in the concentra- 
tion of the acid. But after a time a point is reached beyond 

240i 1 1 1 1 1 1 1 \ 




Hours 
Figure 58. 

which a further increase in concentration is followed by a dimin- 
ished absorption of water. This fact has its analog in the 



ABSORPTION, SECRETION— CELLS AND TISSUES 157 



O o 



si 



OOHOOlfflNO) 

§±±±++±±±3> 

O O O O i-l r-l tH i-l rH 

§±+±±±±+±g> 

dddddi-*'-H'-i'-t_ 

ddrH^TH^I^rHiH 

S3S§sl§21~ 

OOOi-ii-iOOOO 

iiiiiiiiS" 

ooooooooo 
6 do <6 <6 <6 <6 a c> 



2| 



n/10 
f 101 cc. 
I 2 0. 


% 

(0) 

(+ 56.2) 

(+109.1) 

(+119.4) 

(+131.1) 

(+129.9) 

(+112.5) 

(+112.1) 

(+ 99.7) 

f) 

X 


•s 


©NiOiOCDINQOiCO 
00NMO00 001O1ON 


8 cc. n/10 
HCl+102 cc. 
H 2 0. 


% 

0.723 (0) 
1.138 (+ 57.4) 
1.500 (+107.4) 
1.595 (+120.6) 
1.710 (+136.5) 
1.675 (+131.6) 
1.632 (+125.7) 
1.585 (+119.2) 
1.540 (+113.0) 
(f) 

VIII 


5 cc. n/10 
HCl +105 cc. 
H 2 0. 


% 

0.541 (0) 
0.960 (+ 43.6) 
1.387 (+156.3) 
1.532 (+183.1) 
1.720 (+217.9) 
1.780 (+229.0) 
1.650 (+204.9) 
1.480 (+173.8) 
1.285 (+137.5) 
(e) 
VII 


4 cc. n/10 
• HCl+106 cc. 
H 2 0. 


% 

0.491 (0) 
0.815 (+ 65.9) 
1.150 (+134.2) 
1.313 (+167.4) 
1.473 (+200.0) 
1.578 (+221.3) 
1.420 (+189.6) 
1.220 (+148.4) 
1.095 (+123.0) 

(e) 

VI 



! 



158 



(EDEMA AND NEPHRITIS 



absorption of water by fibrin or gelatin in acid solutions of various 

concentrations. 

Table LXIV is given in detail to show by what means were 
obtained all the data upon which conclusions in this section are 
based. The first figure in each of the columns indicates the 
original weight of the muscle. After each of the weighings 
there is given, in parentheses, the gain in weight, expressed in 
per cent of the original weight of the muscle. 

(6) It is somewhat difficult to say what is the effect of alkalies 
on the absorption of water by muscle. The statement is un- 
questionably true that muscle swells more in the solution of any 
alkali than in water. There seems to be a great difference, how- 
ever, both in the swelling of tree toad legs from which the skin 
has been removed and of the gastrocnemius muscles of frog 
with the season. In my original experiments with tree toads 
I got a decidedly greater swelling in dilute alkaline solutions than 
in water. In later experiments (December 11, 1908) with the 
gastrocnemius muscles of winter frogs (Rana) this difference 
was not so marked. I append Tables LXV and LXVI to illus- 
trate this point. In explanation of these results it should be noted 
that the amount of swelling in pure water runs unusually high. 
As, to my mind, this is brought about chiefly through the pro- 
duction of acid within the muscles, the high water absorption 
values indicate an unusually large production of acid (starvation 
acidosis in winter frogs?). When such muscles are placed in 
alkaline solutions, the alkali combines with the acid, and the salt 



TABLE LXV 

Gastrocnemius Muscles of the Frog 



Hours in the 
solution. 


110 cc. H 2 0. 


o cc. n/10 
XaOH+105 cc. 
H 2 0. 


10 cc. n/10 
XaOH+100 cc. 
H 2 0. 








% 


% 




% 










984 (0) 


0.571 (0) 





571 (0) 


1 


05 


1 


397 (+41.9) 


0.858 (+50.2) 





920 (+ 61.1) 


3 


25 


1 


610 (+63.6) 


0.995 (+56.7) 


1 


104 (+ 93.3) 


4 


45 


1 


659 (+68.5) 


0.881 (+54.3) 


1 


144 (+100.3) 


8 


45 


1 


680 (+70.7) 


0.854 (+49.5) 


1 


141 (+ 99.8) 


20 


50 


1 


626 (+65.2) 


0.842 (+47.4) 


1 


108 (+ 94.0) 


34 


10 


1 


540 (+56.5) 


0.838 (+45.9) 


1 


125 (+ 97.0) 


45 


50 


1 


530 (+55.4) 


0.850 (+48.1) 


1 


142 (+100.0) 


70 


20 


1 


510 (+53.4) 


0.885 (+54.9) 


1 


135 (+ 98.7) 



ABSORPTION, SECRETION— CELLS AND TISSUES 159 



8 


^PPSS? Son 


S 

8 





4 cc. n/10 
iOH+106 
H2O. 


% 

. 595 (0) 
.852 (+43, 
,875 (+48, 
,840 (+48, 
,818 (+37, 

820 (+37. 

? ? 
.872 (+46. 
,875 (+47, 
.885 (+48, 


% 

.447 (0) 
,655 (+46. 
715 (+59. 
705 (+57. 
680 (+52. 
642 (+43. 
605 (+35. 
620 (+38. 
610 (+36. 
605 (+35. 




000000 000 




0000000000 






8 


^O^c^coSP^ 


. 

SEE 
05 ^ 


0000000000 


10 cc. n/10 
NaOH +100 
H2O. 


% 

0.461 (0) 
0.675 (+46 
0.710 (+52. 
0.680 (+47. 
0.670 (+45, 
0.660 (+43, 
0.670 (+45, 
0.725 (+57. 
0.755 (+63. 
0.772 (+67. 




00O0N OOOHOO 


8 




2 cc. n/1 
NaOH +108 
H 2 0. 


0000000000 


9 cc. n/l( 
NaOH +101 
H 2 0. 


% 

0.537 (0) 
0.778 (+44, 
0.813C+51 
0.795 (+48. 
0.796 ( +48. 
0.778 (+44. 
0.825 (+53, 
0.870 (+58. 
0.910 (+69 
0.925(+72 


1 cc. n/10 
NaOH +109 cc. 
H2O. 


% 

0.704 (0) 
0.972 (+38.0) 
1.106 (+57.1) 
1.120 (+59.1) 
1.102 (+56.5) 
1.070 (+51.9) 
0.975 (+38.5) 
0.995 (+41.2) 
1.000 (+42.0) 
1.040 (+47.7) 


8 cc. n/10 
NaOH +102 cc. 
H2O. 


% 

0.545 (0) 
0.890 (+63.3) 
0.935 (+71.5) 
0.910 (+66.9) 
0.912(+67.3) 
0.900 (+65.1) 
0.920 (+68.8) 
0.990(+81.6) 
1.020(+87.1) 
1.030(+88.9) 


1/2 cc. n/10 
c. NaOH +109-1/2 cc. 
H2O. 






CO © 01 CO N tJI 10 (N iO 


% 

0.706 (0) 
0.970 (+37. 
1.090 (+54. 
1.100 (+55. 
1.072 (+51. 
1.048 (+48. 

0.970 (+37. 
0.965 (+36. 
0.965 (+36. 


7 cc. n/K 
NaOH +103 
H 2 0. 


% 

0.547 (0) 
0.795 (+45 
0.835 (+52 
0.820 (+49 
0.802 (+46 
0.800 (+46 

O 7Q0 ( -4-4.4 

0.840 (+53 
0.860 (+57 
0.863 (+57 


1/4 cc. n/10 
NaOH+109-3/4c 
H 2 0. 


% 

0.732 (0) 
1.022(+39.6) 
1.150 (+57.1) 
1 . 170 ( +59 . 8) 
1.155(+57.8) 
1.130(+54.3) 
1.030 (+40.7) 
1.032 (+40.9) 
1.028 (+40.4) 
1.015 (+38.6) 


6 cc. n/10 
NaOH +104 cc. 
H 2 0. 


% 

0.558 (0) 
0.818 (+46.5) 
0.822.X +47. 3) 
0.795 (+42.5) 
0.789(+41.0) 
0.770 (+37.8) 
0.845(+51.4) 
0.825 (+47.8) 
0.830 (+48.7) 
0.845(+51.4) 


$ 

i 

S 


oCocqS^o^oooSo" 


g 




% 

0.808 (0) 
1.104 (+36. 
1.265 (+56. 
1.300 (+73. 
1.290 (+59. 
1.260 (+55. 
1.135 (+40. 
1.140 (+41. 
1.130 (+39. 
1.130 (+39. 


5 cc. n/10 
NaOH +105 
H 2 0. 


% 

0.580(0) 
0.885 (+52 
0.918(+58, 
0.900 (+55, 
0.880 (+51 
0.855 (+47 
0.825 (+42 
0.880 (+51 
0.900 (+55 
0.900 (+55 


Hours in the 
solution^ 




1.00 
3.50 
6.35 
8.50 
1 1 Qn 

24.30 
34.50 
58.45 
82.40 


Hours in the 
solution. 





160 



OEDEMA AND NEPHRITIS 



formed by the union inhibits the swelling. (See paragraph c, 
below.) 

Loeb states that the gastrocnemius muscles of frogs swell more 
in the solution of an alkali than in acid solutions of the same 
normality. The few weighings that he gives are not sufficient to 
prove this, for only serial weighings can tell us whether the maximal 
swelling in a muscle has been attained, is being approximated, or 

140 1 1 1 l 1 1 —l 1 1 




20 1- —i I i i i i i ■ 

5 10 15 20 25 30 35 40 45 

Hours 

Figure 59. 

has been passed. The experiments just outlined indicate that, if 
the opposite is not true, the question is at least still an open one. 

(c) The addition of any salt to the solution of an acid decreases 
the amount that a muscle will swell in that solution, and the 
higher the concentration of the salt the greater is the amount of 
this inhibition. Fig. 59 illustrates this fact. The curve marked 
HC1 was obtained by immersing a gastrocnemius muscle in a 
solution of hydrochloric acid, made by adding 10 cc. n/10 hydro- 



ABSORPTION, SECRETION— CELLS AND TISSUES 161 



chloric acid to 100 cc. of water. The three remaining curves 
show the changes in weight suffered by muscles immersed in solu- 
tions made by adding the same amount of acid to 100 cc, respect- 
ively, of m/8, m/4 or m/2 solutions of sodium chlorid. As plainly 
evident, the action of the hydrochloric acid is entirely inhibited, 



140 - 




40 1 • 1 1 1 1 1 1 1 1 1 

5 10 15 20 25 30 35 40 45 

Hours 

Figure 60. 

so far as the absorption of water is concerned when the last-named 
concentration of sodium chlorid is employed. 

(d) While all salts diminish the amount of water absorbed by 
muscle in an acid solution, the different salts are very unequally 
effective in this regard, when equimolar solutions are compared. 
The effect of three acetates on the swelling of tree-toad muscu- 



162 



OEDEMA AND NEPHRITIS 



lature is compared in Fig. 60. The upper curve represents the 
action of a pure n 110 hydrochloric acid solution, made by adding 
10 cc. n 10 hydrochloric acid to 100 cc. water; the remaining 
curves, the effect when the same amount of acid is added, respect- 
ively, to 100 cc. m 4 solutions of potassium, sodium and calcium 




HQ + FeCl s 



10 



15 



20 _ ; 
Hours 

Figuke 61. 



30 



35 



40 



45 



acetate. These salts are effective in reducing the amount of 
swelling in the order named, potassium being less powerful than 
sodium, and this than calcium. It will be remembered that we 
found the same arrangement when the action of different salts 
with a common acid radical on the swelling of fibrin in acid solu- 
tions was compared. 

In Fig. 61 are compared the effects of a series of chlorids on 



ABSORPTION, SECRETION— CELLS AND TISSUES 163 



the swelling of muscle in acid solutions. The hydrochloric 
acid curve stands prominently above that for pure water. All 
the salts bring about a diminution in the amount of swelling, 
but while present in the same molar concentration they are very 
differently effective in this regard. The solutions were all prepared 
by adding 10 cc. n/10 hydrochloric acid to 100 cc. m/4 solutions 
of the various salts. We have no difficulty in recognizing the 
following order in which the diffe en basic radicals are effective, 
that producing the least inhibition being given first: 

Sodium, Ammonium, Calcium, Copper (ic), Magnesium, Iron (ic). 

With the exception of the copper salt the general grouping 
is again similar to that found in studying the effects of different 
salts on the swelling of fibrin and gelatin. That the arrangement 
of the individual radicals is not identical in the two series is not 
surprising, for muscle represents not only a mixture of several 
colloids, but contains several salts. It is, therefore, from both 
a physical and a chemical standpoint a substance not nearly 
so well defined as washed fibrin or gelatin. 

Fig. 62 permits the comparison of a few acid radicals. The 
curves for hydrochloric acid and for water need no special com- 
ment. The solutions containing salts were again prepared by 
adding 10 cc. n/10 hydrochloric acid to 100 cc. of the m/4 
solutions of the required ammonium salts. The order, 

Acetate, Chloric!, Nitrate, Sulphate, 

in which the radical least effective in reducing the swelling in 
an acid solution is named first, is readily recognized. The gen- 
eral grouping is here again the same as in the case of fibrin. 

The relations in muscle are not, however, all as simple as might 
at first appear from this analogy between the swelling of fibrin 
and the swelling of muscle. Fig. 63 has been introduced in 
illustration of this fact. A number of acid radicals may here 
be compared, but as apparent, the order in which this series 
of sodium salts is effective is not an easy one to describe. We 
recognize in the first few hours of the experiment the order familiar 
to us from our study of fibrin, 

Chlorid, Sulphate, Phosphate, Tartrate, 

but in the later hours this is changed to 

Tartrate, Phosphate, Chlorid, Sulphate. 



164 



OEDEMA AND NEPHRITIS 



The causes for this change are not as yet clear. They are 
undoubtedly several in number, dependent in part on differences 
in the rate of diffusion of acids, salts, etc., into and out of the 
muscles; in part, on the fact that muscle after removal from 
the body undergoes spontaneously a series of chemical changes 
through which its physical state is progressively altered. This 
series of curves shows well the dangers inherent in conclusions 
based upon single or too few weighings of muscle at arbitrarily 
chosen intervals. 



120 



100 



SO 



60 



40 







1 1 


— 1 1 1 1 — 






1 \ HC1 








H 2 


t HC1+NH 4 C 2 H 3 2 






y / /^* HC1+NH4C1 " 
1'* - — , HCH+NH4NO3 




* * — ■* _ 


__^HC1+(NH 4 ) 2 S0 4 








5 10 


15 20 25 30 
Hours 

FlGUKE 62. 


35 4( 


> 45 



(e and /) The marked effect of all electrolytes in reducing the 
swelling of a muscle in an acid solution is not shared by non- 
electrolytes. Fig. 64 shows this better than many words. None 
of the curves shows any characteristic change in shape from 
the pure hydrochloric acid curve in spite of the fact that the 
various non-electrolytes are present in amounts osmotically more 
than equal to those of the electrolytes used in the already described 
experiments. In each case 10 cc. n/10 hydrochloric acid were 



ABSORPTION, SECRETION— CELLS AND TISSUES 165 



added to 100 cc. m/2 cane sugar, ethyl or methyl alcohol, urea 
or glycerin. The two monatomic alcohols seem to be entirely 
without effect in the concentrations employed. Glycerin pro- 
duces some inhibition of swelling. The urea curve lies well above 
that for glycerin. The general order in which these non-electrolytes 
affect swelling is therefore again similar to that observed in study- 
ing the swelling of fibrin or gelatin. 

(g) The taking up and giving off of water by muscle represents 
in large part a reversible process. This process, however, is 
not completely reversible (within the time limits of these experi- 

80 1 i t ' 1 11 t ■ 1 1 



60 
40 

20 

*% 


-f, 
20 

40 



HCl+NaCl 



HCl+NaKC 4 K 4 6 
* ? 




HCl+Na 2 S0 4 



10 



15 



20 Hours 25 
Figure 63. 



35 



40 



45 



ments) in that a muscle seems to suffer somewhat permanently 
from every condition through which it is required to pass. This 
statement, which is analogous to that made regarding fibrin, 
is illustrated in Fig. 65. The first part of the curve a, a, a, repre- 
sents the stage of progressive loss of water by a gastrocnemius 
muscle which has passed the point of maximal swelling in a solu- 
tion of n/110 hydrochloric acid. At the place indicated by the 
arrow it is transferred to pure water, in which the muscle is 
observed to gain promptly in weight and so to continue for some 
hours. An explanation of this fact is found when we look at 
Fig. 58 and Table LXIV. A n/110 hydrochloric acid does 



166 



OEDEMA AND NEPHRITIS 



not represent the optimal concentration for the swelling of a 
frog's muscle. To transfer it from such to pure water is to place 
it, at least for a time, under conditions which approximate the 
optimal more nearly (an acid solution below the concentration 
of n 110). 



180 




160 






/ \ HC1 




/ \ ~ a ~ 


140 


1 \ HCT+ Cane Sugar 




/ \ y — \ -a- 


120 


- i \ 


100 




if ^ -_____HCl+aH 5 OH -6- 


80 


// /r — ~^-~______HCl+C H 3 OH -b- 






60 


■ I HCl+Urea -c- 


40 


| HC1+ Glycerin -c- 


20 




n 




5 10 15 20 25 30 35 40 45 




Hours 




Figure 64. 




Curve b, b, b, b, represents the effect of transference from a 



mixture of acid and potassium chlorid to one of acid and calcium 
chlorid, and finally into a pure hydrochloric acid solution. While 
the muscle was steadily increasing in weight in the HC1-KC1 
mixture, it began to lose immediately after transfer to the 
HCl-CaCi2 mixture. When taken out of this and placed in pure 



ABSORPTION, SECRETION— CELLS AND TISSUES 167 



HC1, a gain is noted, but this is not sufficient to make the muscle 
even approximate in weight that originally attained in the 
HC1-KC1 mixture — the muscle recovers only partially from the 
effect of its residence in the hydrochloric acid solution contain- 
ing calcium chlorid. 




HCl 




HC1+ CaCl2 c 



10 f 15 

Hours 

Figure 65. 



Curve c, c, c, c, indicates also the somewhat lasting effect upon 
the muscle of every condition through which it passes. The 
sharp fall in weight upon transference from the pure n/110 hydro- 
chloric acid to the equally concentrated one containing calcium 
chlorid (10 cc. n/10 HC1 + 100 cc. m/2 CaCl 2 ) and the only 
incomplete restitution when returned to the pure acid solution 
is clearly evident in the drawing. 

In curve d, d, d, is found additional evidence for the incomplete 
reversibility of the absorption and secretion of water by muscle. 



168 



(EDEMA AXD NEPHRITIS 



The muscle had steadily lost in weight since being placed in a 
mixture of 10 cc. n 10* HC1 + 100 cc. m 2 CaCl 2 when at the 
point indicated by the arrow it was transferred to pure n 110 
hydrochloric acid. The muscle began to gam immediately, 
but owing to previous residence in the solution containing calcium 
chlorid this gain amounted to little more than a restoration of 
its original weight. 

These paragraphs suffice to prove that the absorption and 
secretion of water by such a tissue as muscle is identical with 
the absorption of water by various protein colloids from a quali- 
tative point of view. We must now consider the quantitative 
aspects of the problem; in other words, prove that the absorption 
of water by such a colloid as fibrin or gelatin is of sufficient mag- 
nitude to account, without strain, for the maximal amounts 
ever absorbed by muscle. The largest amount of water that I 
ever found muscle to take up was less than two and one-half 
times its original weight (246.6 per cent). As fresh muscle con- 
tains about 75 per cent water and about 1 per cent ash, we may 
say, roughly, that one-fourth consists of various organic sub- 
stances. These belong, nearly all of them, to the colloids, and 
to that special half of them known as lyophilic (hydrophilic) or 
emulsion colloids. On the basis of these figures one gram of 
dried muscle substance is equivalent to four grams of moist 
(normal) muscle, which has the power of absorbing enough water 
(250 per cent) to weigh fourteen grams. One part of dry muscle 
substance may therefore absorb thirteen times its weight of 
water. How easily this, which represents the extreme of water 
absorption in muscle, may be accounted for through the power 
of simple colloids to absorb water, is apparent when it is remem- 
bered that fibrin readily absorbs fifteen to twenty times its weight 
of water in dilute acids and as much as thirty (under the best 
circumstances almost forty) times its weight in dilute alkalies. 
The maximal values obtained with gelatin run even higher. It 
absorbs without difficulty even sixty-five times its weight of water. 

This extensive analogy between the absorption of water by 
fibrin or gelatin and the absorption of water by muscle, both 
from a quantitative and a qualitative standpoint, seems to me 
to justify the conclusion that the absorption of water by muscle 
is determined in the main by the state of the colloids contained in it. 



ABSORPTION, SECRETION— CELLS AND TISSUES 169 



But since muscle is only a tissue chosen at random for study, 
the question arises whether the absorption of water by all 
tissues is simply a function of the colloids they contain. We 
shall next attempt to answer this larger question. 

2. The Analogy between the Absorption of Water by Certain 
Protein Colloids and by the Eye 

The eye consists, as is well known, of a series of different 
tissues each characterized by distinctive physical characteristics. 
There is no difficulty in distinguishing between the opaque sclera, 
the clear and transparent cornea, the well-named " glass-like " 
vitreous and the lens. The eye, in consequence, represents a 
collection of tissues which may be utilized as experimental mate- 
rial in our attempt to see if the analogy between the absorption 
of water by certain colloids and the absorption of water by muscle, 
cannot be broadened to embrace an analogy between the ab- 
sorption of water by these colloids and the absorption of water 
by protoplasm in general. 

The following experiments show that the absorption of water 
by the eye is governed by the same laws as the absorption of water 
by fibrin or gelatin. The fresh eyes of sheep, pigs and cattle were 
employed shortly after their removal at the slaughter house. 
For the most part sheep eyes, carefully trimmed of adhering 
tags of muscle and fat, were used, but identical results can be 
obtained with the eyes of pigs or cattle. To avoid useless details 
only the conclusions from many series of experiments are given 
below, and these have been arranged in lettered paragraphs 
corresponding with similarly lettered ones in the sections on the 
swelling of fibrin and of gelatin. What has been said of fibrin 
and gelatin may thus be compared with what is said regarding 
the absorption of water by the eye. 1 

The amount of water absorption was measured by weighing 
the eyes at intervals and calculating the increase or decrease in 
weight in percentage of the original weight of the fresh (moist) 
eyes. The eyes were kept in lightly covered finger bowls con- 
taining enough of the various solutions to cover the eyes. 200 cc. 
are sufficient for sheep eyes, while the large cattle eyes demand 

1 For detailed weighings and figures, see Martin H. Fischer: Pfliiger's 
Arch., 125, 396 (1908); ibid., 127, 1 (1909). 



170 



(EDEMA AND NEPHRITIS 



300 cc. To make the weighings, the eyes were taken out of their 
solutions, carefully dried with soft filter paper and weighed as 
quickly as possible on balanced powder papers, such as are 
employed by pharmacists. ■ 






CO 




LU 




> 




HI 


[- 


Q. 


Is 


UJ 


SHE 



S3 




The following conclusions are of importance in our discussion: 
(a) An enucleated eye absorbs more water in the solution of 
any acid than in distilled water. When equinormal acids are 
compared they are found to be unequally effective in this regard. 
Fig. 66 shows graphically the results of a few such experiments 



ABSORPTION, SECRETION — CELLS AND TISSUES 171 



with n/110 acids. As easily apparent, the swelling in hydro- 
chloric and nitric acids is sufficiently great to lead to a rupture 
of the eyeball — the sclera splits and allows the escape of the 
more fluid contents of the eye. Rupture of the eyeball is indicated 
in this figure and in all that follow by the five-cornered star at 
the end of the curves. Sulphuric, oxalic and acetic acids are 




Honrs 
Figure 67. 

all less potent in making eyes swell, for the absorption curves 
with these acids are decidedly lower, in the order named, than 
those for nitric and hydrochloric acids. In none of these does 
a rupture of the eyes occur at the concentrations employed. The 
curve obtained by immersion of an eye in pure water is introduced 
for comparison. 

The amount that an eye swells in any acid solution is depend- 
ent on the concentration of the acid. This is illustrated in Fig. 67. 



172 



(EDEMA AND NEPHRITIS 



The curve for pure water is the lowermost one. The Roman 
numerals indicate progressively higher concentrations of hydro- 
chloric acid. The solutions were made by adding, 2, 4, 6, 8, 
12, 14 and 16 cc. of n/10 hydrochloric acid to enough water to 
make 220 cc. of solution. The acid solutions vary in conse- 
quence from n/1100 to n/137. A definite increase in the amount 
of swelling with every increase in concentration is readily dis- 
cernible. In the highest concentrations the absorption of water 
is sufficiently great (and sufficiently rapid) to lead to rupture 
of the eye. 

It is of extreme interest to note how low a concentration of 
acid brings about a decided absorption of water by the eye. The 
lowest concentration of hydrochloric acid in this series does not 
betray its acid character to the sense of taste; the second has a 
taste, but it cannot be recognized as sour. It requires imagination 
to recognize the acid taste even in the third concentration in which 
an eye becomes stony hard. 

(6) Eyes swell more in the solution of an alkali than in pure 
water. While there is no question about this fact (see Fig. 68), 
the amount of difference in swelling between an eye in pure water 
and one in the solution of an alkali is not as great as that between 
an eye in water and one in an acid solution. The same explana- 
tion holds for this observation as was given for the difference 
in the amount of swelling of muscle in solutions of acids and 
alkalies. The eye after removal from the body spontaneously 
undergoes an acid change. This acid is neutralized by the alkali 
of the solution into which the eye is dropped, whereby a salt is 
formed, the presence of which inhibits the swelling of the eye in 
the alkaline solution. (See paragraph d, below.) 

The different alkalies affect the swelling of the eyes to unequal 
degrees when equinormal solutions are compared, but the exact 
order in which they are effective is not yet definitely settled. 

If the amounts are compared that an eye will swell in acid 
and in alkaline solutions having, respectively, the same H or OH 
concentration, it is found that an eye swells less in the solution 
of an alkali than in an equally concentrated acid. The curves 
marked HC1 and KOH in Fig. 68 illustrate this, both solutions 
being n/110. The cause for this divergence from the behavior 
of fibrin was touched upon in the preceding paragraph. 

(c) The presence of any salt reduces the amount that an eye 



ABSORPTION, SECRETION— CELLS AND TISSUES 173 



will swell in any acid or alkaline solution. Fig. 68 shows this as 
well as Figs. 69, 70, and 71. The effect of the pure acid or alkali 
(n/110, made by adding 20 cc. of their n/10 solutions to 200 cc. 
of water) is evidenced by the curves marked HC1 and KOH in Fig. 
68. When an eye is placed in solutions made by adding the 



30 



25 



15 



10 







5 



10 



15 









x/ 






• /hci 


SHEEP EYES 
irrm 




\L*^~: . KOH+ jvj a(Jl *- . 




H 2 






^\HC1+Caa 2 





*0 5 10 15 20 25 30 

Hours 



Figure 68. 

same amounts of acid or alkali, respectively, to 200 cc. m/4 solu- 
tions of calcium chlorid or sodium chlorid, the curves marked 
HCl+CaCl 2 and KOH+NaCl are obtained. The curve of ab- 
sorption in pure water is introduced as a control. 

Fig. 69 shows that the higher the concentration of the added 
salt the less does an eye swell in an acid solution. The eye 



174 



(EDEMA AND NEPHRITIS 



bursts in the pure hydrochloric acid solution made by adding 
20 cc. n/10 hydrochloric acid to 200 cc. of water. The remaining 
curves are self explanatory if it is stated that 20 cc. n/10 hydro- 
chloric acid are added in each of these cases to 200 cc. of the appro- 
priate solution of calcium nitrate. 

(d) When the dehydrating effect of equimolar solutions of 
different salts is compared, they are found to be very unequally 




SHEEP EYES 

HCl+Ho m Ca(NQ 3 ) 2 



HCl+^o 111 Ca(NO s ) s 



HCl+Mo m Ca(NOjj) 2 



HCH^o m Ca(NO s ) s 



25 



Figure 69. 



effective in this regard. As in the case of fibrin or gelatin, the 
effect of any salt seems to be made up of the sum of the effects 
of its constituent radicals. Fig. 70 permits comparison of the 
action of different basic radicals. The eyes burst in both the 
pure hydrochloric acid solutions, but in none of those to which 
a salt had been added. The solutions containing salt were made 
by adding 20 cc. n/10 normal hydrochloric acid to 200 cc. m/6 
solutions of the different chlorids. The bases arrange themselves 
in about the following order, in which that least effective in re- 



ABSORPTION, SECRETION— CELLS AND TISSUES 175 

ducing the amount of swelling in an acid solution is placed highest 
in the series, and first in each group: 

1. Lithium, Ammonium, Potassium, Sodium. 

2. Barium, Strontium, Magnesium, Calcium, Copper (ic). 

3. Iron (ic). 




+ 



We have small difficulty in discovering in this table the same 
grouping familiar to us from our discussion of the swelling of 
fibrin and gelatin. 



176 



(EDEMA AND NEPHRITIS 



In Fig. 71 are shown the effects of salts having different acid 
radicals. In each case 20 cc. n/10 hydrochloric acid are again 
added to 200 cc. of m/6 solution of the appropriate sodium salt. 



30 



15 



10 







5 





j 1 1 J 1 1 


/ 

/HOI 

7 


15HEEP EYES 

HCl+NaCl 


V 


HCl+NaBr 




* HCl-hNaNOs 




HCl+NaC 2 H 3 02 


— HCl-t-Na 2 S0 4 


HCl+NaC^HAK .. \ 

1 1 • > ' > • 



)1 U I ' I i i 

5 10 15 20 25 30 35 40 

Hours 
Figure 71. 



Their order is as follows when that least effective in reducing 
the amount of swelling in an acid solution is placed first: 

1. Chlorid, Bromid, Nitrate, Acetate. 

2. Phosphate, Sulphate, Tartrate. 

This table also is to all intents and purposes identical with 
that given in the discussion of water absorption by fibrin and 
gelatin. 



ABSORPTION, SECRETION— CELLS AND TISSUES 177 



(e and /) Non-electrolytes do not share with electrolytes their 
marked power of decreasing the absorption of water by the eye. 
Fig. 72 shows this better than many words. The curves lie 
very closely together, and in spite of the fact that the various 
non-electrolytes are present in amounts which are osmotically 
more than equivalent to the 
powerfully acting electrolytes 
(20 cc. n/10 HC1+200 cc. 
m/3 solution of the non- 
electrolyte), not one of the 
eyes has been kept from 
bursting. 

(g) The absorption and 
secretion of water by the eye 
is largely a reversible proc- 
ess. This is indicated in 
Fig. 73. Curve A shows how 
an eye which has reached 
the bursting point in a pure 
hydrochloric acid solution 
suffers a prompt loss of water 
if taken out of this solution 
and transferred to an equally 
concentrated one containing 
calcium chlorid in addition. 
Curve B shows the reverse 
of this. An eye which has 
gained but little weight in 
pure water is transferred to 
a dilute hydrochloric acid 
solution. Immediately the 

absorption of water is hastened, and becomes so great that the 
eye bursts. The eye, also, suffers somewhat permanently from 
every condition through which it has passed. Once, for example, 
an eye has been in an acid containing a salt, it does not subse- 
quently swell as much in a pure acid solution (in the time 
allowed in these experiments) as it would have done had it been 
placed here directly. 




Figure 72. 



178 



(EDEMA AND NEPHRITIS 



3. The Analogy between the Absorption of Water by Certain 
Protein Colloids and by Nervous Tissue 

The complete analogy between the absorption of water by 
certain protein colloids and by muscle and the eye as outlined in 




Figure 73. 



the preceding sections seemed to me to justify the conclusior 
that the colloids and their state are chiefly if not entirely re- 
sponsible for the amount of water held by any cell, tissue or organ 
under different circumstances. Since this conclusion was first 
voiced, it has found generous acceptance and support from a 



ABSORPTION, SECRETION — CELLS AND TISSUES 179 



number of investigators. 1 But it has also met with opposition. 
Here we must consider the objections of J. Bauer, 2 who believes 
that in nervous tissues water absorption is not, in the main, a 
function of the protein colloids found in them. Before pointing 
out the obvious errors in Bauer's experiments and conclusions, 
let us first look at the following experiments made by Marian 
0. Hooker 3 and me, which, contrary to Bauer's view, show 
that the absorption and secretion of water by nervous tissues (brain 
and spinal cord) is entirely analogous to the absorption and secretion 
of water by such protein colloids as fibrin or gelatin. 4 

To obtain perfectly fresh nervous tissue in as unchanged a 
condition as possible, we used normal rabbits which had been on 
a generous mixed diet, killed them by a gentle blow behind the 
ears and then rapidly dissected out the brain and spinal cord. 
The dura and arachnoid membranes were removed and the pia 
was peeled off as well as possible. The nervous tissues were cut 
into pieces of approximately the same size. In each series of 
experiments the pieces used were always taken from the same 
animal. This is necessary, for comparatively trivial things 
influence the initial state of the nervous tissue. If an animal is 
chased about its cage just before being used, or is ill, its nervous 
tissues show a different capacity for absorbing water, due, in the 
main, we think, to differences in their initial acid content, than 
when such things have not happened. In the same way the stale 
tissues from an animal dead some hours or days show different 
absorption curves (because of a higher initial acid content) than 
fresh ones. 

After weighing, the pieces of tissue were introduced into the 
different solutions. At various times they were taken out, re- 

x See for example: I. Traube: Pfliiger's Arch., 140, 109 (1911); K. 
Gedroiz: Russ. Journ. f. exp. Landwirtsch., 11, 66 (1910). E. Przibram: 
Kolloidchem. Beihefte, 2, 1 (1910). H. Klose: Arch. f. Kinderheilk., 55, 
43 (1910). H. Bechhold: Colloids in Biology and Medicine, translated by 
Bullowa, New York (1919). H. Klose and H. Voigt: Beitr. z. klin. 
Chirurgie,69 (1910) . O. Potzl and A. Schuller: Zeitschr. f . d. ges. Neurologie, 
C (1910). Rudolf Arnold: Kolloidchem. Beihefte, 5, 411 (1914). 

2 J. Bauer: Arb. a. d. neurol. Inst. d. Wiener Univ., 19, 87 (1911); Kol- 
loid-Zeitschrift, 9, 112 (1911). 

3 Marian O. HookiTr and Martin H. Fischer: Kolloid-Zeitschr., 10, 
283 (1912), where detailed weighings may be found. 

4 For further evidence in this direction and independent criticism of 
Bauer's conclusions see Raphael Ed. Liesegang: Ergebnisse d. Neurol, u. 
Psych., 2, 157 (1912). 



180 



(EDEMA AND NEPHRITIS 



weighed and the increase or loss calculated in percentage of 
their original weight. The results are shown in the accom- 
panying curves, which were made by plotting time on the hori- 
zontal and changes in weight on the vertical. As they are all 
drawn to the same scale they may be compared directly with 
each other. 




Figure 74. Figure 75. 



To indicate their complete analogy the following paragraphs 
on the absorption of water by nervous tissue are lettered to 
correspond with the similarly lettered paragraphs in the sections 
on fibrin and gelatin. 

(a and b) When nervous tissue (brain) is placed in distilled 
water it takes this up (gains in weight). We shall at once in- 
terpret this by saying that after removal from the body the 
tissue develops acid and this increases the capacity of the brain 
colloids for holding water. If the brain is placed in a dilute acid 



ABSORPTION, SECRETION— CELLS AND TISSUES 181 

instead of in water it swells decidedly more. With every increase 
in the concentration of the acid the amount of water absorption 
is increased. These facts are brought out in the curves of Fig. 74. 
But the increased swelling with increase in concentration of acid 
continues only up to a certain point, when every further addition 
of acid only reduces the amount of water absorbed. This is 
shown in Fig. 75. The curves of Figs. 74 and 75 are based respec- 
tively upon the experimental data contained in Tables LXVII 
and LXVIII: 



TABLE LXVII 
Adult Rabbit Brain 



Hours in the 
Solution. 


100 cc. H 2 


100 cc. 
1/10000 n HC1 


100 cc. 
3/10000 n HC1 




% 


. % 


% 





1.228 (0) 


1.142 (0) 


0.865 (0) 


1.20 


1.825 ( + 49) 


1.682 (+ 47) 


1.346 (+ 55) 


4.20 


2.336 ( + 90) 


2.247 (+ 97) 


1.765 (+104) 


22.35 


3.775 (+208) 


3.850 (+237) 


1.775 (+221) 


27.00 


4.185 (+240) 


3.950 (+246) 


3.110 (+260) 



TABLE LXVIII 
Adult Rabbit Brain 



Hours in the 


100 cc. 


100 cc. 


100 cc. 


100 cc. 


Solution. 


2/1000 n HC1 


1/1000 n HC1 


5/10000 n HC1 


H 2 




% 


% 


% 


% 





0.630(0) 


0.650 (0) 


0.663 (0) 


1.228 (0) 


1.20 


0.785 (+25) 


0.926 (+43) 


1.005 (+ 52) 


1.825 (+ 49) 


4.20 


0.866 (+38) 


1.066 (+64) 


1.210 (+ 83) 


2.336 (+ 90) 


22.40 


1.030 (+64) 


1.205 (+85) 


1.575 (+138) 


3.775 (+208) 


27.00 


1.090 (+73) 


1.240 (+91) 


1.680 (+153) 


4.185 (+240) 



(c) The amount of acid developed in nervous tissue after 
removal from the body is so near that leading to a maximum of 
water absorption that none needs to be added from the outside 
in our further experiments. If we place the pieces of tissue in 
pure solutions of various kinds we shall in reality be observing 
the effect of these plus that of a certain amount of acid (produced 
by the tissue itself). 

Fig. 76 (as well as Figs. 77, 78, 79, 80, 81 and 82) shows that' 
the addition of any electrolyte to the (acid) solution in which 



182 



(EDEMA AND NEPHRITIS 



brain tissue is swelling reduces the amount of water absorbed. 
This reduction is the greater the higher the concentration of the 
added electrolyte. Fig. 77 shows the same to be true for spinal 



SOr 




Figure 76. Figure 77. 



cord. The experimental data contained in Tables LXIX and 
LXX form the basis of Figs. 76 and 77. 



TABLE LXIX 
Youxg Rabbit Braix 



Hours in the 


120 cc. 


120 cc. 


120 cc. 


120 cc. 


Solution. 


m/2 XaCl 


m.'4 XaCl 


m/6 XaCl 


m/8 XaCl 










% 





O.S08(0) 


0.860 (0) 


0.915 (0) 


0.982 (0) 


2.45 


0.822 ( + 2) 


.945 (+10) 


1.000 (+ 9) 


1.087 f +11) 


5.45 


0.855 ( + 6) 


.9SO (+14) 


1.075 (+17) 


1.212 (+23) 


23.15 


0.977 (+21) 


1 . 141 ( +33) 


1 . 267 ( +38) 


1 . 605 ( +63) 


29.25 


1 . 005 ( +24) 


1.178 (+37) 


1.410 (+56) 


1.715 (+75) 



TABLE LXX 
Spixal Cord of Youxg Rabbit 



(Same Animal as in Table LXIX) 



Hours in the 


120 cc. 


120 cc. 


120 cc. 


Solution. 


m/2 XaCl 


m/4 XaCl 


m/8 XaCl 












% 


% 







0.072(0) 


0.081 (0) 


0.142 (0) 


3.00 


0.057 (- 2) 


0.092 (+13) 


0.192 (+35) 


5.30 


0.0S0 (+11) 


0.100 ( +23) 


0.200 (+41) 


23.20 


0.086 (+20) 


0.112 (+38) 


.230 (+62) 


29.25 


0.090 (+26) 


0.120 (+48) 


0.242 (+70) 



ABSORPTION, SECRETION— CELLS AND TISSUES 183 



(d) Equimolar concentrations of different salts reduce in 
very unequal degree the' swelling of nervous tissue (in any acid 
solution). 

In Figs. 78, 79 and 80 some salts are compared having the 
same basic, but different acid radicals. In Fig. 78 the sodium 




L 1 1 1 1 l _J i_ 

Hours 6 12 18 21 30 36 42 



Figure 78. 

salts are seen to arrange themselves in the following familiar 
order when that least effective in preventing swelling is given 
first: 

Chlorid, Nitrate, Acetate, Phosphate, Sulphate. 
In Fig. 79 the potassium salts assume the following order: 
Chlorid, Acetate, Citrate. 

Or in Fig. 80: 

Bromid, Iodid, Sulphocyanate, Nitrate. 

The dehydrating action of salts having the same acid radical 
but different bases is compared in Figs. 81 and 82. In the 



184 



(EDEMA AND NEPHRITIS 



chlorid series when the salt least effective in inhibiting swelling 
is given first, we see the order: 

Ammonium, Sodium, Potassium, Strontium, Barium, Magnesium, Copper, 

or in the nitrate series similarly arranged: 

Ammonium, Potassium, Sodium, Strontium, Magnesium, Barium, 
Calcium, Iron. 

The dehydrating action of these salts on nervous tissue is prac- 
tically identical, therefore, with their dehydrating action on fibrin 
or gelatin. 




i i i i 1 1 

Hours 6 13 18 24 30 



Figure 79. Figure 80. 



Figs. 78, 79, 80, 81 and 82 are based respectively upon the 
data contained in Tables LXXI, LXXII, LXXIII, LXXIV, 



ABSORPTION, SECRETION— CELLS AND TISSUES 185 




OHours 6 12 18 24 30 36 42 48 



Figure 81. 
TABLE LXXI 



Brain of Rabbit 



Hours 
in the 
Solution. 


100 co. 

m/6 
Na 2 S0 4 


100 cc. 
m/6 
Na 2 HP0 4 


100 cc. 

m/6 
NaC 2 H30 2 


100 cc. 

m/6 
NaNOa 


100 cc. 

m/6 
NaCl 


100 cc. 
H 2 




2.00 
3.00 
20.15 
24.10 
44.35 
68.15 


% 

0.766 (0) 
0.766 (0) 
0.752 (- 2) 
0.771 ( + 1) 
0.781 (+ 2) 
0.820 ( + 7) 
0.855 (+10) 


% 

0.751 (0) 
0.741 (- 1) 
0.755 (+ 1) 
0.827 (+10) 
0.826 (+10) 
0.910 (+21) 
0.966 (+28) 


% 

1.220 (0) 
1.251 (+ 3) 
1.270 (+ 4) 
1.565 (+29) 
1.580 (+30) 
1.710 (+40) 
1.825 (+50) 


% 

1 . 200 (0) 
1.291 (+ 8) 
1.310 (+10) 

1.639 (+36) 

1.640 (+37) 
1.825 (+52) 
1.975 (+65) 


% 

0.752 (0) 
0.799 (+ 3) 
0.837 (+11) 
1.063 (+41) 
1.087 (+44) 
1 . 202 ( +59) 
1.265 (+68) 


% 

1 . 120 (0) 
1 . 595 ( + 42) 
1 . 780 ( + 59) 
2.821 (+152) 
2.814 (+151) 
3.195 (+185) 
3.223 (+188) 



186 



(EDEMA AND NEPHRITIS 




Figure 82. 



ABSORPTION, SECRETION — CELLS AND TISSUES 187 



TABLE LXXII 



Brain of Rabbit 



Hours in the 
Solution. 


120 cc. m/6 
Calcium citrate 


120 cc. m/6 
Calcium acetate 


120 cc. m/6 
Calcium chloric! 


120 cc. H 2 




% 


% 


% 


% 





1.086(0) 


0.685(0) 


1.072(0) 


0.623 (0) 


2.30 


0.992 (-8) 


0.770(+13) 


1.308(4- 22) 


1.100(4- 78) 


5.35 


0.995 (-8) 


0.815(+20) 


1.410(4- 31) 


1.450(4-133) 


23.50 


1.060 (-2) 


1.033(4-51) 


1.753(4- 63) 


2.075(4-233) 


28.25 


1.060 (-2) 


1.050(+54) 


1.795(4- 68) 


2.165(4-247) 


47.30 


1.120 (+3) 


1.160(4-70) 


2.005(4- 87) 


1. 858 »( 4- 198) 


71.20 


1.185 (+9) 


1 . 245 ( 4-82) 


2.170(4-102) 


1.690H4-171) 



1 Going into solution. 



TABLE LXXIII 



Brain of Rabbit 



Hours in 
the solu- 
tion. 


120 cc. 

m/6 
KNO3 


120 cc. 

m/6 
KCNS 


120 cc. 
m/6 
KI 


120 cc. 
m/6 
KBr 


120 cc. 
H2O 




% 


% 


% 


% 


% 





1.241 (0) 


1.105 (0) 


0.712(0) 


. 773 (0) 


0.623 (0) 


2.30 


1.388 (4-12) 


1.286(4-17) 


0.863 ( 4-21) 


0.916(4- 18) 


1.100 (4- 78) 


5.35 


1.510(4-22) 


1.363(4-23) 


0.978(4-37) 


1.047 (4- 35) 


1.450 (4-133) 


23.30 


1.822(4-47) 


1 . 693 ( 4-53) 


1.235(4-73) 


1.350 (4- 74) 


2.075 (4-233) 


28.25 


1.973 (4-59) 


1.713 (4-55) 


1.200 (4-68) 


1.395 (+ 80) 


2.165 (4-247) 


47.30 


2.125 (4-71) 


1.867(4-69) 


1.285 (4-80) 


1.475 (4- 91) 


1.8581 (4-198) 


71.20 


2.245(4-81) 


2.070(4-88) 


1 . 375 ( 4-93) 


1.590(4-106) 


1.6901 (4-171) 



Going into solution. 



TABLE LXXIV 



Adult Rabbit Brain 



Hours in the 
Solution. 


120 cc. m/6 
CuCl 2 


120 cc. m/6 
MgCl 2 


120 cc. m/6 
BaCh 


120 cc. m/6 
SrCl 2 




1.30 
18.15 
26.00 
47.15 
67.60 


% 

0.791 (0) 
0.775 (-2) 
0.753 ( -5) 
0.747 (-6) 
0.749 (-5) 
0.765 (-3) 


% 

0.685 (0) 
0.692 (4- 1) 
0.723 (4- 6) 
0.730 (4- 7) • 
0.810 (4-18) 
0.887 (4-30) 


% 

1.010 (0) 
1.010 (0) 
1.155 (4-14) 
1.217 (4-20) 
1.297 (4-28) 
1.450(4-43) 


% 

0.878 (0) 

0. 910(4- 4) 
1.005 (4-14) 
1.083 (4-23) 
1.158 (4-32) 

1 . 230 ( 4-40) 


Hours in the 
Solution. 


120 cc. m/6 
KC1 


120 cc. m/6 
NaCl 


120 cc. m/6 
NH4CI 


120 cc. H2O. 




1.30 
18.15 
26.00 
47.15 
67.60 


% 

0. 998 (0) 
1.023 (4- 3) 
1.337 (4-34) 
1.430 (4-43) 

1 . 600 ( 4-60) 
1 . 832 ( 4-84) 


% 

0.558 (0) 
0.625 (4-12) 
0.793 (4-42) 
0.815 (4-46) 
0.910(4-63) 
1.017(4-82) 


% 

0.788 (0) 
0.883 (4- 12) 
1.385 (4- 76) 
1.365(4- 73) 
1.530(4- 94) 
1.710(4-117) 


% 

0.526 (0) 
0.875 (4- 63) 
1.708 (+213) 
1.945 (+263) 
1.8721 (+250) 
1.642 1 (+206) 



1 Going into solution. 



188 



(EDEMA AND NEPHRITIS 



TABLE LXXV 
Adult Rabbit Brain 



Hours in the 
solution. 


120 cc. m/6 
Fe(NOs)3 


120 cc. m/6 
Ca(N0 3 ) 2 


120 cc. m/6 
Ba(N0 3 ) 2 


120 cc. m/6 
Sr(N0 3 ) 2 


120 cc. m/6 
Mg(NO»)2 




3.45 
22.45 
27.45 
46.15 
70.15 


% 

0.575 (0) 
0.495 (-14) 
0.362 (-37) 
0.332 (-42) 
0.278 (-51) 
0.240 (-58) 


% 

0.785 (0) 
0.842 (+ 8) 
0.955 (+22) 
0.960 (+22) 
1.020 (+30) 
1.060 (+35) 


% 

0.535(0) 
0.575 (+ 7) 
0.660 (+23) 
0.673 (+26) 
0.705 (+31) 
0.763 (+43) 


% 

0.820 (0) 
0.867(+ 5) 
1.035 (+26) 
1 . 105 ( +35) 
1.158 (+41) 
1.283 (+58) 


% 

0.742 (0) 
0.765 (+ 3) 
0.887 (+20) 
0.965 (+30) 
1.072 (+45) 
1.215 (+64) 



Hours in the 


120 cc. m/6 


120 cc. m/6 


120 cc. m/6 


120 cc. 


solution. 


NaNOs 


KNOs 


NH4NO3 


H 2 




% 


% 


% 


% 





0.610(0) 


0.758(0) 


0.828 (0) 


0.370 (0) 


3.45 


0.708 (+16) 


0.975 (+ 29) 


1.155 (+ 39) 


0.810 (+117) 


22.45 


0.970 (+60) 


1.288(+ 70) 


1.465 (+ 79) 


1 . 505 ( +306) 


27.45 


1 . 005 ( +65) 


1.350 (+ 75) 


1.525 (+ 84) 


1.560 (+322) J 


46.15 


1.135 (+86) 


1.485 (+ 95) 


1.742 (+110) 


1 . 745 ( +372) 


70.15 


1 . 205 ( +97) 


1.565 (+105) 


1.7321 (+109) 


1.910 (+420) 



1 Going into solution. 



(e and/) At the same concentration the non-electrolytes are 
far less powerful in reducing the swelling of nervous tissue (in 
an acid medium) than the electrolytes. Fig. 83 and Table LXXVI 
show this. Even though the three alcohols were present in a 
concentration osmotically equal to or higher than that of the 
electrolytes used in the experiments previously described, a 
decrease in the amount of swelling is either not evident at all or 
but slight. As both the figure and the table indicate, urea seems 
actually to favor the absorption of water. 

TABLE LXXVI 
Adult Rabbit Brain 



Hours 
in the 
solution. 


120 cc. m/3 
Glycerin 


120 cc. m/3 
Urea 


120 cc. H 2 


120 cc. m/3 
Methyl 
Alcohol 


120 cc. m/3 
Ethyl 
Alcohol 




4.00 
23 .45 
28.00 
46.30 
70.30 


% 

0.832(0) 
1.153 (+ 39) 
1.902 (+130) 
2. 188 (+163) 
2.595 (+210) 
2.904 (+249) 


% 

0.828 (0) 
1.560 (+ 81) 
2.347 (+183) 
2.3151 (+179) 
2.510 (+203) 


% 

1.227 (0) 
2.200 (+ 79) 
3.475 (+183) 
3.840 (+213) 
4.345 (+255) 
4.2801 (+248) 


% 

0.905 (0) 
1.572 (+ 73) 
2.605 (+189) 
2. 830 (+213) 
3.200 (+253) 
3 . 288 ( +263) 


% 

0.978 (0) 
1.782 (+ 82) 
2.982 (+205) 
3 . 252 ( +232) 
3.695 (+277) 
3.935 (+303) 







1 Going into solution. 



ABSORPTION, SECRETION— CELLS AND TISSUES 189 




Figure 83. 

TABLE LXXVII 
Adult Rabbit Brain 



Hours in the 
solution. 



120 cc. 
H 2 



120 cc. m/6 
NaCl 



120 cc. m/6 
NaCl 



120 cc. 
H2O 








2 


25 


3 


25 


4 


20 


6 


00 


24 


00 


25 


45 


29 


35 


47 


45 



% 

1 . 150 (0) 
2.030 (+76) 
2.050 (+78) 
Transferred 



1.970 (+ 71) 
2.090 (+ 82) 
2.467 (+114) 



% 



1 . 670 ( +45) 
1.630 ( +41) 
1 . 845 ( +59) 
Transferred 



% 

1 . 100 (0) 
1.260 (+15) 
1.305 (+19) 
Transferred 



2.075 (+89) 
1.920 (+75) 
1 . 700 ( +55) 



1.480(+ 35) 
1.760 (+ 60) 
2. 830 (+157) 
Transferred 



190 



(EDEMA AND NEPHRITIS 



(g) The absorption and secretion of water by nervous tissue 
represents in large part a reversible process. This is brought out 




Figure 84. 

in Figs. 84 and 85 and Tables LXXVII and LXXVIII, upon which 
these drawings are based. If nervous tissue is placed in a dilute 




Figure 85. 



acid or in water (which amounts to placing it in a dilute acid) 
it swells. If, after any desired degree of swelling has been 
attained, the tissue is transferred to an equally concentrated 



ABSORPTION, SECRETION— CELLS AND TISSUES 191 



acid containing a salt, the swelling ceases and a loss of water 
begins. If now the tissue is returned to the pure acid or to 
water, rapid absorption again occurs. A reverse set of facts 
and curves is obtained if the tissue is first placed in acid plus 
salt, then in pure acid and then again in acid plus salt, as is 
also evident in Figs. 84 and 85. 

TABLE LXXVIII 



Adult Rabbit Brain 



Hours 
in the 
solution. 


120 cc. m/6 
NaCl +0.2 cc. 
n/10 HC1 


120 cc. H 2 

+0.2 cc. 
n/10 HC1 


120 cc. H2O 
+0.2 cc. 
n/10 HC1 


120 cc. m/6 
NaCl +0 . 2 cc. 
n/10 HC1 




2.30 
3.30 

4.20 
6.00 
23.45 

25.45 
29.45 
47.45 


% 

1.517 (0) 
1.730 (14+) 
1.765 (16+) 
Transferred 


% 

2.015(+ 33) 
2.370 (+ 56) 
3.295 (+117) 
Transferred 


% 

1 . 280(0) 
2. 180 (+70) 
2.370 (+85) 
Transferred 


% 

1.950 (+52) 
1 . 890 ( +48) 
2.070 (+62) 
Transferred 










2.333 (+54) 
2.205 (+45) 
2.247 (+48) 


2.217 (+ 74) 
2.430 (+ 90) 
2.993 (+134) 



These experiments dispose, we think, of Bauer's objections 
which have been taken up in detail elsewhere. 1 His conclusion 
that acids only dehydrate nervous tissue was reached because 
he chose his acid concentrations too high (beyond those optimal 
for brain swelling), and because he worked with stale tissues 
(six to twenty-four hours old) so rich in postmortem acids that a 
further addition of acid from the outside could only decrease 
their power of swelling. 

In concluding these paragraphs, attention may be directed 
to Fig. 86, which shows how enormously brain tissue can swell. 
The figure shows the two halves of a young rabbit's brain and 
spinal cord split longitudinally. The half marked a was care- 
fully protected from evaporation, that marked b was kept in a 
n/ 10,000 lactic acid solution. At the end of twenty-four hours 

1 Marian O. Hooker and Martin H. Fischer: Kolloid-Zeitschr., 10, 292 
(1912). 



192 



(EDEMA AND NEPHRITIS 



it had gained twice its original weight (200 per cent) in water. 
Since fatal brain cedemas show an increase in weight of less than 




b 

Figure 86. 



10 per cent it is readily apparent how easily such may be accounted 
for on the basis of colloid swelling. 



ABSORPTION, SECRETION— CELLS AND TISSUES 193 



IV 

THE BIOLOGICAL SIGNIFICANCE OF THE ANALOGY BE- 
TWEEN THE ABSORPTION OF WATER BY CERTAIN 
PROTEIN COLLOIDS AND THE ABSORPTION OF WATER 
BY DIFFERENT TISSUES 

1. Introductory Remarks 

The complete analogy from both a quantitative and a quali- 
tative point of view between the absorption of water by certain 
colloids and by widely differing types of tissues seems to me 
to warrant the conclusion that the colloids and their state are the 
main factors concerned in determining the amount of water held by a 
cell, a tissue, an organ or a whole individual under different physio- 
logical or pathological circumstances. 

That they might be of some importance in this regard has 
occurred to several observers, but careful study of their papers 
shows that for the most part they dismissed the thought with 
little more than mere reference to its possible role, or the added 
remark that its significance in the general problem could not be 
great. Interestingly enough W. Pfeffer, 1 who worked so ear- 
nestly for the establishment of the importance of osmotic pressure 
as the great regulator of the water content of cells, seems to have 
been the first to regard the pressure of swelling (Quellungsdruck) 
as of use in explaining various exceptions to the laws of osmotic 
pressure as studied in botanical material. Later Franz Hof- 
meister 2 developed the same idea experimentally in his now 
classic and fundamental discussions of the biological significance 
of the colloid state. Durig 3 expressed the belief that studies on 
the swelling of colloids might help to explain the exceptions to the 
laws of osmotic pressure noted in his experiments on the absorption 
of water by frogs in various solutions. Rudolf Hober 4 and E. 

1 W. Pfeffer: Pflanzen Physiologie, Leipzig, 1, 116 (1897); see also the 
first edition of 1881, 1, 26 to 29. 

2 F. Hofmeister: Arch. f. exp. Path. u. Pharm., 28, 210 (1891). 
3 Durig: Pfliiger's Arch., 85, 401 (1901). 

4 R. Hober: Physikalische Chemie d. Zelle u. d. Gewebe, 2d Ed., 61, 
02 and 70, Leipzig, (1906); Koranyi-Richter's Physikalische Chemie u. 
Medizin, 1, 294, Leipzig (1907); Hober' s latest writings condemn the colloid- 
chemical view of water absorption and my support of it entirely. Biol. 
Zentralbl., 31, 575 (1911). 



194 



(EDEMA AND NEPHRITIS 



Overton 1 also considered the subject. Both, however, laid great- 
est stress on the osmotic conception of water absorption by cells, 
especially as modified by the belief that the osmotic membrane 
about cells is fat-like (lipoid) in character. The role of the colloids 
is by both these authors not considered the fundamental factor in 
absorption, but is simply pointed to as one useful in explaining 
some of the many exceptions found to exist between the actual 
and the theoretical behavior of cells when these are regarded as 
osmotic systems. Much the same position is taken by H. J. 
Hamburger. 2 The colloids as a factor in the regulation of the 
water content of organs have also been discussed by Wolfgang 
Ostwald 3 and Wolfgang Pauli. 4 Pauli pointed out that 
the swelling of red and white blood corpuscles in solutions of a 
dilute acid is not unlike the swelling of certain colloids, but in 
his discussion of the swelling of muscle he decided against this 
being essentially a colloid phenomenon because the analogy 
between the swelling of muscle and the swelling of certain colloids 
was not sufficiently close. His unfortunate conclusion was due to 
the fact that he compared the careful observations at hand on 
the swelling of gelatin with a group of inadequate observations 
on the swelling of muscle. 

The experiments just detailed on the analogy between the 
absorption of water by protein colloids and by muscle, eyes and 
nervous tissue constitute, so far as I know, the first attempt to 
establish experimentally not only the quantitative, but the quali- 
tative importance of the colloids of the tissues in determining 
the amount of water held by them. From a quantitative stand- 
point, we found that certain (hydro philic) protein colloids are 
readily able to absorb amounts of water which are larger than 
any we have to account for in protoplasm, and from a quali- 
tative standpoint we found that the behavior of protoplasm 
toward various external conditions, so far as its water content 
is concerned, is no different from the behavior of some simple 
colloids toward the same external conditions. 

The individual cell which we call an ameba is, in its pond 

*E. Overton: Nagel's Handbuch der Physiologie, 2, 744, Braunschweig 
(1906), where references to his earlier papers will be found. 

2 H. J. Hamburger: Osmotischer Druck und Ionenlehre. See especially 
3, 4 to 33, 50 to 54 and 108 to 144, Wiesbaden (1902 to 1904). 

3 Wolfgang Ostwald: Personal Communication. 

4 Wolfgang Pauli: Ergebnisse der Physiologie, 6, 126 to 129 (1907). 



ABSORPTION, SECRETION— CELLS AND TISSUES 195 

water, like a fibrin flake floating in a solution of some kind. Let us 
add acid to the medium in which the ameba lives and it swells 
as does the fibrin flake ; or let us add salt, and both shrink. The 
aggregate of cells which we call tissues, or organs, behave simi- 
larly. Only for the words pond water we need to substitute 
blood or lymph, for this is the medium in which the cells of our 
body lie and from which they absorb as does the ameba an 
amount of water which is determined by the nature and the 
state of the colloids found in the cells. But to accept the ab- 
sorption of water by colloids as the most important factor in the 
absorption of water by the tissues is to arraign all the explanations 
which have thus far been given for the normal and abnormal 
variations in the amount of water held by protoplasm. We 
must, in consequence, study them for a moment in order to see 
if the conception which we have introduced of the variable capacity 
of the colloids for holding water merely adds to the forces already 
considered as active in protoplasm or whether the acceptance of the 
ideas here advanced necessitates a revision of our former beliefs. 

We can at once dismiss as purposeless all " explanations " 
which are of a " vitalistic," " neovitalistic " or " physiological " 
character — they are mere salves for the undiagnosed sore. Of 
clearly defined physical or physico-chemical explanations, two 
have assumed special prominence. The first of these originated 
with the plant physiologists and has been widely adopted by the 
animal physiologists. We may call it for short the osmotic 
theory of water absorption, and with it consider that modification 
of it which has come with the belief that the semipermeable 
membrane assumed to surround cells is fat-like (lipoid) in char- 
acter. The second was born of the pathologists, and may be 
called the pressure theory. As we need to discuss it in detail 
later we dismiss it temporarily and here consider only the osmotic 
theory. 

2. Criticism of the Osmotic Theory of Water Absorption by 

Protoplasm 

The osmotic theory has until rather recently represented 
the best attempt to analyze in physico-chemical terms the proc- 
esses of absorption and secretion by living cells. As espoused 
to-day by different workers, it has suffered strange and self- 



196 



(EDEMA AND NEPHRITIS 



contradictory modifications from the original form in which it 
was put forward by Wilhelm Pfeffer and Hugo de Vries, 
but the work of these two continues the foundation upon which 
the moderns have built, and if we would not get lost in termin- 
ology we must consider their work first. 

In order to account for the " turgor " (that is, the water 
content) of plant cells Pfeffer and .de Vries held them to be 
surrounded by " osmotic " " membranes " of such character 
that while they gave passage to water they did not permit sub- 
stances dissolved in this water to go through. On such basis 
they explained the swelling of plant cells in water or dilute solu- 
tions or their shrinkage in concentrated ones by saying that in 
the former water is sucked into the cell, while in the latter it is 
sucked out. The movement of water into or out of the cell 
occurs until the (osmotic) concentration of the dissolved sub- 
stances is the same on both sides of the membrane postulated 
to exist about the cells. But, in order to permit the water to 
move, this membrane must be impermeable to the dissolved 
substances (otherwise, of course, they would simply move from 
a region of higher concentration to one of lower concentration, 
and so osmotic differences could not come to pass, and con- 
sequently no movement of water). 

From these observations and theoretical views sprang the 
interest of the physical chemists in the whole problem of osmosis, 
and we see constructed the various " osmotic cells " that may be 
seen in any physico-chemical laboratory. Pfeffer was again 
pioneer here. He conceived the idea of supporting the " pre- 
cipitation membranes "■ that Moritz Traube had described 
before him in the walls of a porous pot in order to enable them 
to withstand pressure. Such " precipitation membranes " may 
be made of many different substances, but the best and commonest 
is prepared by allowing the solution of a copper salt and the 
solution of a ferrocyanid to move into the wall of a porous pot 
from opposite sides. Where they meet a precipitate of copper 
ferrocyanid is deposited. The copper solution may now be 
washed out of the pot and the ferrocyanid rinsed off the outside. 
In the wall of the pot remains a " precipitation membrane " of 
copper ferrocyanid. This membrane allows water to pass 
through it easily, but it will not permit substances dissolved 
in this water to get through. The membrane is therefore " semi- 



i 



ABSORPTION, SECRETION— CELLS AND TISSUES 197 



permeable/' and so identical with the " osmotic " membrane 
postulated by Pfeffek to surround the living cell. If the labora- 
tory cell is filled with a solution of any kind and placed in water, 
water is sucked into the cell; if it is placed instead into a stronger 
solution, water is sucked out. When equally concentrated solu- 
tions exist within and without, no movement of water occurs. 
As readily apparent, this behavior corresponds, when viewed super- 
ficially, with what Pfeffer and de Vries observed in living cells. 

Pfeffer made many osmotic measurements with his labora- 
tory cell, and on the basis of his observations Van't Hoff some 
years later formulated his famous laws. These are as follows: 

(1) At constant temperature the osmotic pressure of dilute 
solutions is proportional to the concentration of the dissolved 
particles. 

(2) At the same temperature equal volumes of all dilute 
solutions having the same osmotic pressure contain the same 
number of dissolved particles. 

(3) At constant volume the osmotic pressure of any solution 
increases as the absolute temperature. 

The work and conclusions of Van't Hoff and the physical 
chemists now became retroactive and the attempt was made 
to apply the laws of Van't Hoff not only to the biological facts 
that de Vries and Pfeffer had furnished in their studies of 
plant cells, but also to those added by Hedin, Hamburger, 
Gryns, Koeppe, Loeb, Hober, Overton, Webster, etc., in 
their work with various animal cells. To this end the observa- 
tions made on plant and animal cells were compared with those 
made on the laboratory osmotic cell. When a solution of any 
electrolyte or non-electrolyte was found not to change the volume 
of liquid in a laboratory osmotic cell it was said to be " isosmotic " 
with its contents. Any series of solutions thus isosmotic with 
the contents of the osmotic cell were therefore isosmotic with 
each other (and therefore equally concentrated). Similarly, 
when a solution of any kind was found not to change the volume 
of a living cell it was said to be " isotonic " with the cell contents. 
In this way the solutions of many different substances were 
compared and their " isotonicity " determined. If the laws 
of osmotic pressure were active in living protoplasm it was to 
be expected that all "isotonic " solutions should prove to be 
" isosmotic." 



198 



(EDEMA AND NEPHRITIS 



When the first rough comparisons were made it was, in fact, 
thought that the isotonic solutions were isosmotic, but this 
conclusion could not stand the pressure of more careful and more 
numerous observations. To-day we may safely say that we do not 
know a single cell for which the laws of osmotic pressure are valid. 

We need not go into details to prove this. If cells obeyed 
the laws of osmotic pressure they ought always to have the same 
volume in isosmotic solutions of different substances. Exceptions 
to this conclusion are the rule. This was first proved for the 
red blood corpuscles by Koeppe and is corroborated for muscle 
by the experiments of Loeb, Webster, Overton and my own, 
as described in the earlier pages of this book. Again, with every 
increase in the concentration of the medium surrounding a cell 
we should get a proportionate decrease in the volume of the cell. 
As a matter of fact, the shrinkage is always less than anticipated. 
Koeppe found that red blood corpuscles always shrink less than 
expected when the concentration of the surrounding medium is 
raised. The same is true of muscle, living frogs (Durig), enu- 
cleated eyes, nerve tissue and amputated frog legs. While in 
the osmotic cells of our physico-chemical laboratories electrolytes 
and non-electrolytes are equally active when the same number 
of dissolved particles are present in the unit volume, this is not 
the case in living cells. Generally speaking, the electrolytes 
are here active out of all proportion to the non-electrolytes. 

But aside from these physico-chemical facts which stand so 
immovably against any belief which sees in living cells a replica 
of the artificial osmotic cells of our laboratories, biological con- 
siderations make the whole conception impossible. To have 
the laws of osmotic pressure tenable for living cells we must 
have semipermeable membranes about them. Only as this is 
the case can changes in osmotic pressure become available for the 
movement of water into and out of cells. If now, for the sake of 
argument, we grant this assumption, then no dissolved substances 
can get into or out of the cell. Such a conception of the cell is 
impossible, for how under such circumstances could it get its 
necessary food, or how could it rid itself of its various metabolic 
products? Both processes are absolutely indispensable for the 
continuation of life. To get around the difficulty various ob- 
servers have made these osmotic membranes permeable to some 
or many dissolved substances. But the moment we grant this, 



ABSORPTION, SECRETION— CELLS AND TISSUES 199 



then the dissolved substances can diffuse from regions of higher 
to regions of lower concentration, and so differences in osmotic 
pressure are equalized and no forces remain available for the 
movement of water. The adherents to the view that " osmotic " 
membranes exist about cells can take their choice, they can either 
utilize their conception^ to make water move or they can make their 
membranes permeable and so have dissolved substances move, but 
they cannot have both. Yet for life to go on in the cell both processes 
must be able to go on uninterruptedly. 

A further argument against any belief in semipermeable 
membranes about cells is found in the fact that in no cell studied 
has such ever been found by the examining eye. 

The morphological cell wall is admittedly not concerned in 
the osmotic activities of the cell. Usually the layer of proto- 
plasm just inside this is considered the so important semiper- 
meable membrane. This layer in plants differs in appearance 
from the rest of the cell protoplasm no more than the outermost 
edge of a leukocyte or an erythrocyte differs from the rest of the 
cell body. But in spite of this negative morphological finding 
such a semipermeable membrane might still exist. Such a sup- 
position, however, encounters trouble as soon as the fact is re- 
called that when a cell is cut in pieces or when the contents of a 
cell are squeezed out into a solution of any kind, these cell frag- 
ments (which assume a spherical shape) behave just as the 
uninjured cell did before. This observation, which it seems to 
me points decisively against the existence of semipermeable 
membranes, has been accounted for by saying that the fragments 
form a new semipermeable membrane about them as soon as 
they come in contact with the solution into which they are dropped 
— supposedly in much the same way as new precipitation mem- • 
branes may be formed in physico-chemical experiments. But 
in physical chemistry this formation of new precipitation mem- 
branes is not so universal an affair; it occurs only when two 
so-called membrane-forming solutions are brought in contact 
with each other, and it is hard to conceive of protoplasm being 
able to form a semipermeable membrane with just any solution 
with which it is brought in contact. The attempt may be made 
to meet this objection by saying that it is the universally present 
fat-like constituents (the lipoids) of the tissues which go to form 
the membrane when the cell fragments are dropped into any 



200 



(EDEMA AND NEPHRITIS 



watery solution, but as we shall soon see, the permeability of 
the lipoids to dissolved substances is far too limited to help us 
much toward an understanding of the phenomena that we are 
discussing. 

An enormous literature has sprung up about this question 
of " membranes " surrounding cells. From the original osmotic 
membranes of Pfeffer, which were semipermeable, we have 
come to those which are partially permeable and then to those 
which are permeable sometimes and then again not. But even 
these complicated notions encounter trouble, for there is so little 
connection between the kind of substances that enter cells and 
those that do not. Only the members of one group — that which 
has a ready solubility in the fats — have been recognized as having 
one property in common, and to account for their ready entrance 
into the cells the osmotic membrane about cells has been endowed 
with lipoid characteristics. The unfortunate part about this 
theory, which is in essence that of E. Overton, is that while it 
renders easier our conception of the absorption of these lipoid- 
soluble substances, it makes it impossible to get the ordinary 
salts and water into cells, for these are not particularly soluble 
in these lipoids. Overton has, in fact, come to such a con- 
clusion. And yet we know from physiological and pathological 
facts that all these types of substances must be able to get into 
cells. 

Moreover, what do we gain when we have succeeded in getting 
any dissolved substance or water through any kind of membrane 
postulated to exist about a cell? It would collect here and we 
should still have to account for the movement of the dissolved 
substance or the water into or through the rest of the cell proto- 
plasm. There are no membranes about cells. All the phenomena 
which are difficult to explain when we assume membranes to exist 
about cells are readily interpreted without recourse to such postu- 
lates on the basis of the colloid constitution of protoplasm. 

In answer to these arguments some of my critics have retorted 
that a " membrane " exists whenever two phases come in contact 
with each other. At this point we have to stop and define terms, 
for here the argument begins to become academic. A drop of 
any fluid, a drop of any colloid solution, a drop of protoplasm 
or a cell has a " membrane " about it, but this " membrane " 
is simply a surface tension film; it has nothing in common with 



ABSORPTION, SECRETION— CELLS AND TISSUES 201 



the " osmotic " membranes that in turn the botanists, the physical 
chemists and the original animal physiologists who worked in 
this field talked about. These surface tension films are chemically 
identical with the rest of the cell protoplasm and (except as colloid 
particles tend to collect in these surface films and so raise their 
concentration here) as -such behave toward water or dissolved 
substances exactly as does the rest of the cell protoplasm. 

These facts indicate clearly that there is little reason for accepting 
the osmotic theory as of paramount or even great importance in ex- 
plaining the ways and means by which tissues absorb or secrete 
water. 

I would like to be correctly understood in this matter. I am 
not maintaining that the laws of osmotic pressure may not account 
for some of the phenomena observed in at least some cells. This 
is a question which on the basis of the experimental data now 
available cannot be decided, but the biological significance origi- 
nally attributed to these laws has certainly been much overrated. 
Nor does such a decision against the role of osmotic pressure 
in these biological phenomena minimize in the slightest the value 
of the work of that score of investigators who have busied them- 
selves with this problem — they have made not only the best effort 
to analyze physico-chemically the forces active in the absorption 
and secretion of water by the cell and its myriad associated prob- 
lems, but they have laid down the experimental data upon which 
all subsequent workers on this problem must build. 1 

3. Criticism of the Lipoid Membrane Theory 

In an attempt to meet the inadequacies of the osmotic theory 
of water absorption by protoplasm, E. Overton 2 assumes that 
the surface of cells is made up of a substance which in its prop- 
erties as a solvent is not unlike ether or the fatty oils. He was 
led to this conclusion in attempting to account for the fact that 
many substances when dissolved in water are unable to " plas- 
molyze " cells. For example, while the various salts, at a suitable 
concentration, lead to a shrinkage of plant cells, a large number 

1 For new and striking evidence against the osmotic notion of water 
absorption by cells see Wade W. Oliver: Science, 40, 645 (1914). 

2 E. Overton: Vierteljahresschr. d. naturf. Gesellsch. zu Zurich, 40, 1 
(1895); 44, 88 (1899); Zeitschr. f. physik. Chem., 22, 189 (1897); Pnuger's 
Arch., 92, 261 (1902); Nagel's Handbuch der Physiologie, 2, 2te Halfte, 
744 to 896 (1907). 



202 



(EDEMA AND NEPHRITIS 



of other chemical compounds, such as urea, glycerin, various 
sugars and alcohols do not do so. 

Believers in the osmotic theory of de Vries and Pfeffer 
explain this exceptional behavior by saying that the membranes 
assumed to exist about cells are permeable to this group of sub- 
stances. Overton has tried to define the nature of this per- 
meability by pointing out that all these substances have the 
property in common of being soluble in fats and fat-like bodies, 
and as such are universally present in protoplasm (as the lipoids — 
lecithin, cholesterin, protagon, cerebrin), he has tried to account 
for the permeability of cells to these substances by saying they 
go through these cell membranes because they are soluble in 
them. Most salts, he says, do not go through because they are 
insoluble in this surface film, in consequence of which they may 
extract water from the cell and so lead, at the right concentra- 
tion, to its plasmolysis. 

The difficulty with Overton's explanation is that in account- 
ing for the entrance of the lipoid-soluble substances, he makes 
it impossible to explain the entrance of that much larger group, 
of which the acids, alkalies and salts are representatives, the 
vast majority of which are not soluble in fat-like bodies. Even 
our foodstuffs and the products of cell metabolism belong in 
good part in this group. Yet, judging from physiological experi- 
ments, we know that these must be able to enter cells, otherwise 
how could we account for the normal life or the marked varia- 
tions in it which we are able to produce by means of these very 
substances? It is not enough to say that any or all of these 
substances move only through the intercellular substances. 
That certain substances in certain tissues may move more easily 
through the intercellular substance than through the cells them- 
selves is not questioned — salts, for example, do not diffuse with 
the same ease through different colloids — but that does nob alter 
the main contention that salts and many other substances not 
soluble in the lipoids can and do pass into and through the cells 
themselves. 

Again, the assumption that cells are surrounded by a fat-like 
membrane makes it impossible to account for the entrance or 
exit of water from the cell. Water is not soluble in the fats (except 
theoretically), and hence cannot pass through a layer of it, and 
yet we know that in exceedingly short periods of time cells are 



ABSORPTION, SECRETION— CELLS AND TISSUES 203 



capable of absorbing or secreting enormous amounts of water. 
The attempt might be made to explain this absorption of water 
by calling attention to the colloid properties of at least some 
of the lipoids — lecithin, for example, which is capable of absorbing 
water when dropped into it (Hober). But as soon as we accept 
this as true then our reasons for the non-entrance of the salts fall 
away, for when a lipoid absorbs water it loses at the same time its 
property of being solvent only for lipoid-soluble substances. 

What, again, do we attain when such have penetrated the 
lipoid surface membrane? We accomplish only an accumulation 
of the absorbed substance within the membrane itself, and just 
inside of this. We have then to explain how it gets through the 
rest of the cell. 

In the attempt to harmonize these conflicting notions, Na- 
thansohn 1 has assumed the surface of cells to represent a sort 
of mosaic, a part of which is formed by fat-like substances, another 
by " protoplasmic material " possessed of the properties of a semi- 
permeable membrane. The objections that must be raised against 
Nathansohn's conception are clearly a combination of those that 
were formerly raised against the osmotic conception alone, plus 
those that can be lodged against Overton's modification of it. 

The view of Nathansohn is, however, valuable because it 
brings out the idea of a mixture in protoplasm of substances 
having fat-like characteristics with such as do not possess this 
property. But to confine this mixture to the surface of cells 
is wrong because too limited. We encounter no difficulty in ex- 
plaining the various experimental facts at our disposal by ignoring 
altogether the existence of semipermeable or partially permeable 
membranes about cells. The substance of a cell consists of a mixture 
of different colloids. A part of these are colloid proteins with physical 
and chemical properties like those of fibrin, gelatin, etc.; a second part, 
colloid lipoids, which, while sharing some of the properties possessed 
by the proteins, as their power of swelling in water, have specific 
properties, such as their better power to take up substances soluble only 
in the fat-like bodies; a third part is made up of the colloid carbo- 
hydrates. 2 

1 Nathansohn: Pringheim's Jahrbiicher, 39, 607 (1904). A review is 
found in Hober: Physikalische Chemie d. Zelle u. d. Gewebe, 2d Ed., Leipzig, 
176 (1906). 

2 For a more detailed discussion than is possible in these pages of the 
problem of fat in the cells see Martin H. Fischer and Marian O. Hooker: 



204 



(EDEMA AND NEPHRITIS 



4. Adequacy of the Colloid-chemical Theory of Absorption and 

Secretion 

Let us now see what sort of a substitute for, or addition to, 
our present conceptions regarding the forces active in absorption 
and secretion is found in the role of the hydrophilic colloids. 
What can the colloid-chemical theory of water absorption do 
with the unexplained physiological facts detailed above? 

Two substances have always stood out prominently as ex- 
ceptions to the laws of osmotic pressure as considered active in 
protoplasm, the acids and the alkalies. The various tissues 
which have been examined in their dilute solutions all show an 
absorption of water vastly greater than can be accounted for on 
the basis of osmotic pressure. In fact, the amount that muscle 
can swell in dilute acids has been employed by Overton as a 
conclusive argument against the ordinary osmotic conception 
of water absorption by different tissues. He has pointed- out 
that were all the proteins, carbohydrates and fats contained in 
muscle split into their simplest products, a sufficient yield of 
molecules and ions would not be obtained to f urnish an osmotic 
pressure adequate to account for the amount of water absorbed. 
We have no trouble in explaining this behavior cf acids and alkalies 
on a colloid basis. The acids and alkalies are among the sub- 
stances most powerful in increasing the hydration capacity of 
protein colloids. In this way we can account for the large 
amounts of water absorbed in the presence of traces of acid or 
alkali by red and white blood corpuscles, spermatozoa, muscle, 
the epithelial cells of the bronchi, intestine, bladder or esoph- 
agus, etc. 

There is also no difficulty in accounting for the unequal swelling 
of cells in osmotically equivalent solutions. This is true of the 
swelling of such simple proteins as fibrin, gelatin and gluten. 
In fact, the same substances which exhibit an exceptional be- 
havior in the " osmotic " study of cells show a like behavior in 
the case of simple proteins. 

To find an analog for the failure of muscle, red blood cor- 

Science, 43, 468 (1916); Fats and Fatty Degeneration, New York (1917). 
The role of the colloid carbohydrates is also ignored in this discussion because 
little of immediate interest to us has as yet been done with them. They are 
unquestionably of tremendous physiological and pathological importance, 
not only in plants but in animals as well. 



ABSORPTION, SECRETION— CELLS AND TISSUES 205 



puscles and cells in general to shrink the calculated amount with 
every unit increase in " osmotic " concentration is also simple. 
We need only to refer once more to the swelling of fibrin or of 
gelatin in which we found that here, too, doubling the con- 
centration did not halve the volume — the amount of decrease 
was always less than anticipated. 

In making the colloids responsible for the amount of water held 
by the tissues we escape all need for membranes. 

We can dispense with them in considering the absorption and 
secretion of water by cells just as we can in considering the ab- 
sorption and secretion of water by powdered fibrin or gelatin. 
Nor are we surprised when fragments of a cell behave toward 
external conditions as did the whole; in fact, we expect this, 
for colloids constitute the body of the cell, and just in so far 
as the colloids in the different parts of the cell do not differ from 
each other, in so far also do we not expect the processes of ab- 
sorption and secretion in these various parts to differ. The 
absence of a visible membrane does not annoy us — it simply 
indicates homogeneity of the protoplasm. The presence of a 
visible (not simply " osmotic ") membrane (such as a cellulose- 
cell wall) interests us much more. It introduces another col- 
loid, and with it all the possibilities arising therefrom, for all 
colloids, so far as water absorption is concerned, do not react 
in the same way either quantitatively or qualitatively toward 
any given set of external conditions. For this reason the proto- 
plasfh of a plant cell shrinks away from the surrounding cellulose 
wall when immersed in a concentrated salt solution, and is limited 
in its subsequent expansion if removed to water, for the col- 
loids constituting the cellulose wall are not affected in so marked 
a way by low concentrations of acid, alkali or salt, as is the proto- 
plasm within it. The possibility of explaining the whole problem 
of inequalities in the amount of water held by different parts 
of the same cell therefore evidences itself here. 

What holds for the single cell holds also for different cells, in 
consequence of which we are not surprised when with variation 
in the colloid constitution of different cells we find a correspond- 
ing difference in their behavior when subjected to the same set 
of external conditions. Under normal circumstances different 
cells contain unequal amounts of water, and in states of ex- 
cessive turgor (oedema) neighboring, but morphologically differ- 



206 



(EDEMA AND NEPHRITIS 



ent cells may show most unequal degrees of swelling. Whether 
we deal with different parts of the same cell or with different 
cells does not matter, we need no semipermeable or other kind 
of membrane to explain this. The absorptive powers of the 
various hydrophilic colloids are simply not the same or a colloid 
common to all the cells has been made to swell more in one place 
than in another by changes in its surroundings. 

Let it be added that we are now able to explain the variations 
in the water content of the much neglected intercellular sub- 
stances. In discussing water absorption by cells the intercellular 
substances are all too often overlooked, and this in spite of the 
fact that under physiological conditions some of the largest 
amounts of water are stored in tissues containing few cells (as 
the bell of the jelly-fish or Wharton's jelly of the umbilical 
cord), while in pathological states the very tissues in which cells 
are fewest, and intercellular substance most conspicuous, may 
grow richest in water. We need but recall the intense cedemas 
of connective tissue or the pathological changes v characteristic 
of myxcedema. If we bear in mind that these intercellular 
substances are, like the cells themselves, but mixtures of different 
hydrophilic colloids, none of this surprises us. 

5. Absorption and Secretion of Dissolved Substances by 
Protoplasm. 

Thus far we have discussed only the absorption and secretion 
of water. We have now to consider the dissolved substances in 
the water. To emphasize what should be self evident, we cannot 
and must not consider the absorption or secretion of water and the 
absorption or secretion of a substance dissolved in the water as iden- 
tical processes. Workers in biology make this mistake constantly. 
The processes of the absorption of water and of the absorption of 
dissolved substances do not parallel each other in simple physico- 
chemical experiments, and so need not, and do not, in living cells. 
The two are frequently associated, and may at times lie so closely 
together that they give the impression of running parallel with 
each other, but they are at all times independent of each other 
and may even take place in opposite directions at the same time. 
As we shall see later, a tissue may be absorbing a salt while it is 
secreting water, or vice versa. 

For the absorption of water by tissues we have made the 



ABSORPTION, SECRETION — CELLS AND TISSUES 207 



hydrophilic colloids and changes in their state chiefly responsible. 
The colloid proteins appropriate the lion's share in this matter, 
but the colloid lipoids and the colloid carbohydrates, 1 in so far 
as they have capacity for holding water, must not be ignored. 

The absorption of dissolved substances is quite independent 
of the amount of water absorbed (except as the absorbed water 
retains the characteristics of ordinary water and so increases 
the bulk of solvent available for water-soluble substances in the 
cell). Since in our criticism of the osmotic theory of water 
absorption we have incidentally destroyed the mechanism which 
different authors have used to explain the peculiarities noted 
in the absorption and secretion of dissolved substances by proto- 
plasm, we need to state how on the colloid basis we are going to 
account for them. 

The troublesome element in the whole problem is summed 
up in the observation that when any soluble substance is intro- 
duced into a living organism it does not distribute itself uni- 
formly throughout that organism. When we drop a crystal of 
some dye into a cylinder of water we know that after a while 
the dye by a process of diffusion comes to have the same con- 
centration in all parts of the liquid. The same dye (or any other 
substance, be this oxygen, a salt, a foodstuff or a medicinal agent) 
introduced into a living animal spreads through its tissues by a 
process of diffusion also, yet in the end one organ or one type 
of cell or different parts of one and the same cell may be 
stained to different degrees. Supporters of the osmotic theory 
have tried to account for such phenomena by saying that the 
osmotic membranes about cells possess a " selective permea- 
bility " which lets some substances through while it holds others 
out. In this way they believe dissolved substances to be kept 
apart in neat but differently concentrated packages throughout 
the living organism. But since we found it necessary to give up 
our belief in such membranes, we have to seek an explanation 
on another basis. Concentration differences can be maintained 
in different parts of the same cell, between different cells or between 
cells and their surrounding media even in the absence of " mem- 
branes " because of inequalities in distribution, determined by 
solubility, adsorption or chemical differences, or all three together. 

What this means may be illustrated as follows : 

1 See footnote 2, page 203. 



208 



(EDEMA AND NEPHRITIS 



(a) Inequalities in Distribution Due to Inequalities in Solubility 

When a solution of iodin in water is covered with a layer 
of ether and the whole is shaken, we can see even with the 
naked eye that the iodin is ultimately present in different con- 
centrations in the two liquids. While scarcely any remains in 
the water, the ether assumes a deep color from the iodin. The 
process is simply a homely illustration of the everyday chemical 
procedure of " shaking out with an immiscible liquid." The 
extraction of the iodin from the water depends upon the fact 
that iodin is soluble in ether, and so decidedly more so in this 
than in water that practically all moves over into the ether phase. 
The ultimate state of equilibrium attained, characterized by this 
very unequal distribution (partition) of the dissolved substance 
between the water phase and the ether phase, is in this case simply 
due to the difference in the relative solubilities of the iodin in 
the two solvents. The proportion of iodin dissolved in each of 
of the two phases — in this case a concentration of iodin about 
nine times as high in the one as in the other — is always constant. 
We call this the distribution coefficient or coefficient of partition. 

In discussing the living cell we have so far spoken of its solvent 
powers chiefly from the standpoint of its water content. If the 
cell had solvent powers determined only by its water content, 
it is obvious that dissolved substances could never appear in it 
in higher concentrations than those in which these substances 
are present in the media surrounding the cell. But such a con- 
ception of the cell is too limited. In addition to water, most of 
the various cells of all living organisms contain fat, and the 
already mentioned fat-like bodies known as lipoids (lecithin, 
cholesterin, cerebrin, protagon). We can see in advance that 
living cells containing fats or lipoids must be able to take up 
(that is, dissolve or absorb) many substances which are better 
soluble in such fats and lipoids than in water, in greater amounts 
than the media surrounding these cells which are not so rich in 
or lack these compounds entirely. 

We are indebted to Hans Meyer 1 and E. Overton 2 for 
recognizing the great physiological importance of the facts here 

iHans Meyer: Arch. f. e6cp. Path, und Pharm., 42, 109 (1899); ibid., 
46, 338 (1901): 

2 E. Overton: See reference on page 201. 



ABSORPTION, SECRETION— CELLS AND TISSUES 209 



outlined. By methods which we need not discuss here, they 
found it possible to differentiate between substances which pass 
into or through cells but slowly and those which do this rapidly. 

To the compounds which diffuse rapidly into protoplasm 
belong the monatcmic alcohols, aldehydes and ketones, the 
hydrocarbons with one, two and three chlorin atoms, the nitro- 
alkyls, the alkylcyanids, the neutral esters of inorganic and many 
organic acids, anilin, etc. The diatomic alcohols and the amins 
of monatomic acids pass into cells more slowly, and still more 
slowly glycerin, urea and erythrite. The hexatomic alcohols, 
the sugars with six carbon atoms (hexoses), the amino-acics 
and the neutral salts of the organic acids diffuse into cells only 
very slowly. 

A glance at this list shows that we have to deal with all manner 
of chemical substances. Some are relatively simple in composi- 
tion while others are very complex; some are of physiological 
importance and found normally in the living cell; others are 
entirely foreign to the living organism. What physico-chemical 
character have they in common which allows them to penetrate 
living cells with more than usual ease, and so to stand out from 
the great group of the ordinary neutral salts, for example, which 
do so only slowly? They are all more soluble in fat solvents 
than in water, and therefore pass into and through cells contain- 
ing fats and lipoids more rapidly than into and through such as 
do not. With a given cell the rapidity and the absolute amount 
of any compound ultimately absorbed must depend upon its 
relative solubility in water and in the fat or fat-like bodies con- 
tained in the cells. In other words, it depends upon what is its 
distribution coefficient between the two phases whether any dis- 
solved substance will enter a cell slowly or rapidly, and whether 
it will ultimately be found in the cell in a greater, in the same or 
in a lower concentration than in the medium surrounding it. 

The importance of these simple facts is self evident. In 
order that a substance may produce any physiological effect it 
must first get into the cell. Other things being equal, a quicker 
and more powerful effect will be produced by a lipoid-soluble 
preparation than by one not thus soluble. 

The marked effects of the anesthetics (chloroform, ether, 
alcohol, ethyl chlorid) and of various alkaloids (morphin, cocain, 
atropin) is associated with their fat and lipoid solubility. The 



210 



(EDEMA AND NEPHRITIS' 



nervous tissues are high in fat and fat-like bodies, and so take up 
these substances with special avidity. Because of his greater 
stock of fat solvent, the fat individual demands more anesthetic 
before going to sleep than does a lean one. Anesthesia, like all 
intoxication, is a matter not of absolute amount of anesthetic 
present, but of concentration. The various grades of anes- 
thesia go hand in hand with definite concentrations of anesthetic 
in certain cells of the nervous system, and it must evidently take 
longer to attain this concentration in a fat man than in a lean one. 

(b) Inequalities in Distribution Due to Inequalities in Adsorption 

Not only may a living cell come to contain in the unit volume 
a greater or less amount of any dissolved substance than does the 
surrounding medium because the cell contains better or worse 
solvents for it, but the cell may do this because of its adsorptive 
powers. These adsorptive powers are associated with the fact 
that the cell is largely colloid. The general problem of adsorp- 
tion may be illustrated as follows: 

When a dye is dissolved in distilled water a uniformly colored 
solution results. If the solution is divided and to one-half is 
added a little finely-powdered charcoal while nothing is done with 
the other, we find after shaking both that while the control 
solution remains entirely unaltered, the color largely disappears 
from the other. The decolorization has not been chemically 
induced; the pure carbon does not react chemically with any 
of the constituents in the tube. The powdered charcoal has a 
great surface, and the action of this upon the dissolved particles 
of dye has made them accumulate (condense) upon it. The 
theory of how this surface action is accomplished need not interest 
us here. 

What has been described is an example of adsorption. The 
charcoal is the adsorbent, the dye, the adsorbed substance. 

Any number of substances could be cited as acting under 
various conditions as adsorbents; and almost any substance 
may act as the material capable of being adsorbed. Finely- 
divided kaolin, precipitates of various kinds and inorganic or 
organic colloids may take the place of carbon in the above ex- 
periment, and acids, alkalies and salts can be adsorbed in the 
same way as the readily visible dye. All adsorbents do not, 



ABSORPTION, SECRETION— CELLS AND TISSUES 211 



however, behave qualitatively or quantitatively in exactly the 
same way toward any given material to be adsorbed, and dif- 
ferent external conditions modify markedly the adsorption ex- 
hibited by any given adsorbent. Examples of adsorption are 
familiar to everyone. The commercial decolorization of beers, 
sugars, etc., by animal charcoal; the removal of color from a 
bath by dipping wool, cotton, etc., into it (dyeing) ; the staining 
of histological specimens are all examples of adsorption. 

The adsorption of any substance by an adsorbing agent is 
never complete. Charcoal never takes all the dye out of a bath; 
some always remains behind. The distribution of the dye be- 
tween the solvent and the adsorbent is governed by the laws 
of equilibrium. After the charcoal has taken up as much of the 
dye as possible, if the supernatant liquid is poured off and pure 
water is substituted for it, then some of the dye leaves the char- 
coal and goes back into solution in the water. In this way we 
can again wash all the dye out of the charcoal. Conversely, 
when the charcoal has taken up as much dye as it will from a 
given dye bath, it will proceed to take up an additional amount 
if more dye is added to the supernatant liquid. 

The relationship between the concentration of the substance 
to be adsorbed and the amount taken up by the charcoal is an 
interesting one and may be thus stated: From relatively dilute 
solutions the adsorbent will take up much, from more concentrated 
solutions relatively less, of the substance to be adsorbed. In 
other words, if at a certain concentration we can take four-fifths 
of the dye present in a solution out of this with a given amount 
of charcoal, then if the dye has a higher concentration we can 
take out only less than four-fifths, or if it has a lower concen- 
tration, more than four-fifths. 

Protoplasm behaves toward substances dissolved in a medium 
that surrounds it in an entirely similar way. Upon this depends 
the fact that it may contain the same, a higher or a lower con- 
centration of any dissolved substance than the medium sur- 
rounding it. Since the protoplasm (adsorbent) of different cells is 
not the same, it comes to pass that while they are all bathed by 
the same blood and lymph they nevertheless do not all adsorb 
the same amount of the proffered materials. In other words, 
equilibrium is not attained between the protoplasm - of different 
cells and the medium surrounding these at exactly the same 



212 



(EDEMA AND NEPHRITIS 



point. Hence it comes to pass that the salt content of the 
blood, or its content of a dye, a chemical or an immune body, 
may not only be unlike that of the cells, but that it need not 
be the same in different cells. 

The adsorption properties of protoplasm are markedly in- 
fluenced by various external conditions 1 exactly as are those of 
a laboratory adsorbent. Thus, if acid is introduced into proto- 
plasm, its adsorption powers change markedly. In this way a 
cell or tissue which, under normal circumstances, acts as an ex- 
cellent adsorbent for a dissolved substance, may practically lose 
this property or, conversely, one which before adsorbed a given 
substance only poorly may now take this up with avidity. 

(c) Inequalities in Distribution Due to Specific Chemical Differences 

A third reason why a cell may contain substances in a higher 
(or lower) concentration than the medium surrounding it resides 
in the fact that it contains substances capable of combining with* 
the proffered dissolved substance. Thus, if a cell contains iron, 
it may be expected to take up more of a proffered substance 
capable of combining with this iron (say a ferrocyanid) than a 
cell devoid of it or containing it in less amount. We need not 
multiply such illustrations, for the list is as long as the list of 
chemical reactions capable of ensuing between the various sub- 
stances found in any living cell and the substances that come 
normally or abnormally in contact with it. 

The " specific absorption " and consequent " specific effect " 
of various pharmacological preparations, of " toxins," of " fer- 
ments," etc., is generally regarded as an expression of such in- 
equalities in distribution due to specific chemical differences. 2 
This point of view is largely correct, but it is well to emphasize 
that it is likely to be carried too far. We are still too strongly 
under the influence of the " purely chemical " point of view in 
this matter. We have already learned that many of the " spe- 
cific " immune reactions are not so intensely " specific "; and the 

1 See page 644, and such works as L. Pelet-Jolivet: Die Theorie des 
Farbeproz esses, Dresden (1910). 

2 Paul Ehrlich: Sauerstoff-Bedurfnis des Organismus, Leipzig (1885); 
Deutsch. med. Wochenschr., 597 (1898); Collected Studies on Immunity, 
translated by "Bolduan, New York (1907). Heinrich Zangger: Viertel- 
jahresschr. d. naturforsch. Gesellsch. in Zurich, 53, 408 (1908). 



ABSORPTION, SECRETION— CELLS AND TISSUES 213 



whole realm of colloid-chemistry is dotted with examples of 
reactions that were looked upon as " chemical," when further 
analysis showed that the " specific" in these reactions did not 
depend so much upon the presence of certain chemical com- 
pounds as upon the physical states in which the components 
entered into the reactions. 

Were we at this point to sum up our conception of the structure 
of protoplasm as thus far developed, we could liken it fairly accu- 
rately to a mass of protein intimately mixed with more or less fat- 
like material (the fats and lipoids) and carbohydrates (glycogen), 
the whole being under physiological conditions immersed in a liquid 
(pond water in the case of an ameba, or lymph and blood in the case 
of our body cells) from which the protein-fat- carbohydrate mixture 
soaks up a certain amount of water as well as a certain amount of 
the various dissolved substances found in the water. The water 
absorption is governed by the state of the hydrophilic colloids. The 
absorption of dissolved substances is a matter of equilibrium between 
the concentration of those found in the medium outside the cell and 
that of the same substances found in the cell itself. We have indi- 
cated how solubility characteristics, phenomena of adsorption and 
chemical combination influence the point at which equilibrium is 
reached. This simple picture of the cell furnishes to our minds 
an adequate conception of its main structure. 



PART THREE 
(EDEMA 



PART THREE 

(EDEMA 



I 

INTRODUCTION 

The foregoing pages have brought evidence indicating that 
the colloids of the tissues and their state are chiefly if not entirely 
responsible for the amount of water they hold under various 
conditions. The problem of oedema is also but a problem in colloid- 
chemistry, the problem of the ways and means by which the normal 
hydration capacity of the body colloids is heightened. 

We have had occasion to discuss the great contributions 
first made by the plant physiologists and later adopted by the 
animal physiologists to this general question of excessive turgor 
as observed in various cells. We have now to consider the con- 
tributions made by the pathologists to this same question, which 
they, however, discuss under the heading of oedema. 

I deem it purposeless to review in detail all their theories. 
Such a task would not be easy, for the contentions of the various 
authors cannot always be stated in brief and do them justice. 
Too often this is because they have mixed their excellent experi- 
mental findings with the particular hypothesis which they were 
attempting to make into a theory; and too often also do we 
find good attempts to account for cedema on a mechanical basis 
mixed with the vague conceptions of the activities of " living " 
protoplasm. Any effort, therefore, to analyze the contributions 
of an author to the general subject of the nature and the cause 
of cedema must distinguish carefully between the value of that 
which he may have contributed to the experimental side of the 
subject and to the theoretical. 

Richard Bright made one of the first attempts to account for 
cedema when he tried to find in the loss of albumin from the 
body in nephritis a cause for the thinning of the blood (hydremia). 
Such hydremic blood, he reasoned, would then pass easily through 
the blood vessels and into the tissues, and so cause the latter to 

217 



218 



(EDEMA AND NEPHRITIS 



swell. An experimental investigation of Bright's hypothesis 
forms the basis of the much-discussed work of Julius Cohnheim 
and Ludwig Lichtheim. 1 These authors found that the injection 
of enormous quantities of sodium chlorid solution into the veins 
of various animals did not bring about an cedema similar in dis- 
tribution to that observed in ^right's disease, and so decided 
that hydremia alone, or a hydremia connected with an increase 
in the amount of blood circulating in the blood vessels (hydremic 
plethora), could not be responsible for the cedema of nephritis. 
Experiments carried out by a number of authors since the work of 
Cohnheim and Lichtheim confirm, in the main, their findings. 

For the older hydremic theory, Cohnheim and Lichtheim 
substituted what we may call for short the pressure theory of 
oedema so widely accepted by pathologists to-day. Briefly 
formulated, it holds that variations in the pressure of circulating 
liquids (such as the blood or lymph) are chiefly responsible for 
the variations in the amount of water held by the tissues, in that 
through changes in pressure the circulating liquids are supposed 
to be forced through the vessel walls into the tissues. It is not 
strange that this belief should have originated and seemed espe- 
cially acceptable to those biological workers whose interest 
centers particularly in animals which possess the conspicuous 
feature of a circulatory system. But the very school which 
originally laid most stress upon this force — the school of patholo- 
gists and the earlier physiologists — has found its efforts to increase 
the amount of water held by tissues through an increase by 
experimental means of the blood and lymph pressures, to result 
in failure. 

To meet the deficiency there was therefore added to the changes 
in pressure a second element — a change on the part of the in- 
volved tissues themselves. Thus Cohnheim himself recog- 
nized that severe cedemas occur in animals when no alteration 
whatsoever in blood pressure is apparent. To account for them 
under such circumstances he invoked an " increased permeability 
of the blood vessel walls." Such a belief has never been proved 
experimentally, and, indeed, of what consequence would it be 
from a pathological standpoint? To force liquids through blood 
vessel walls is not to force them into the tissues. And the fluid 

1 Julius Cohnheim and Ludwig Lichtheim: Virchow's Arch., 69, 106 
(1877); also Cohnheim: Allgemeine Pathologie, 2d Ed., 1, 430, Berlin (1882). 



(EDEMA 



219 



of an oedematous tissue is very decidedly in the tissues them- 
selves. Cohnheim's hypothesis would simply squeeze the oedema 
fluid as far as the outer wall of the capillaries. 

A series of other observers have expressed the tissue factor 
in yet other terms. We read that in addition to changes in blood 
pressure there are also necessary for the development of oedema 
a " loss of elasticity " on the part of the tissue, a " decreased 
ability to hold back water," a " heightened imbibition," etc. 
But none of these authors had any clear-cut notion of just how 
these factors were operative. W. S. Lazarus-Barlow's 1 crit- 
ical and experimental observations are noteworthy in this con- 
nection. After emphasizing that anemia of a part as determined 
by ligation of an artery is commonly followed by oedema and after 
verifying this observation by experimentally occluding the blood 
supply to a dog's limb he made the further deduction that an 
accumulation of " metabolic products " in the affected portion in- 
creased such oedema. The latter point he verified by removing the 
two gastrocnemii from a frog, stimulating the one and keeping the 
other at rest. On subsequent immersion of the pair in a physiolog- 
ical salt solution the stimulated muscle was found to absorb more 
water than the non-stimulated. Whether such results were due 
to a " vital process or one depending upon the osmotic coefficient 
of the substances produced," Lazarus-Barlow could not say. 

In 1898 Jacques Loeb 2 tried to explain oedema in the terms 
of the osmotic theory of water absorption by defining it as a state 
of increased water absorption due to an increased osmotic pressure 
of the cell contents. This was the same explanation which 
Hamburger, 3 von Limbeck, 4 Gurber 6 and Eijkman 6 had 
previously used to account for the excessive swelling of various 
cells when subjected to the action of acid or various other changes 
in their surroundings. Its inadequacy was pointed out by E. 
Overton 7 when he showed that were all the proteins, carbo- 

1 W. S. Lazarus-Barlow: Brit. Med. Jour., 1, 634 and 691 (1895). 

2 Jacques Loeb: Pnuger's Arch., 69, 1; 71, 457; 75, 303 (1898). 

3 H. J. Hamburger: Arc. f. (Anat. u.) Physiol., 513 (1892); 153 (1893); 
Zeitschr. f . Biol., 35, 252 and 280 (1897), where references to his earlier papers 
are found. See also Arch. f. (Anat. u.) Physiol., 31 (1898). 

4 C. von Limbeck: Arch. f. exp. Path. u. Pharmakol., 35, 309 (1894). 

5 Gurber: Sitzberich. d. med. phys. Gesellsch. Wurzburg, Feb. 25 (1895). 

6 C. Eijkman: Virchow's Arch. f. path. Anat., 143, 448 (1896), where 
references to his earlier papers will be found. 

7 E. Overton: Pfliiger's Arch., 92, 115 (1902). 



220 



(EDEMA AND NEPHRITIS 



hydrates and fats contained in our tissues split into their simplest 
molecules, enough molecules and ions would not result to yield 
a sufficient osmotic concentration to account for the amounts of 
water absorbed by such swollen (cedematous) cells. Following 
this criticism Loeb in republishing his papers struck out all his 
views on oedema. 1 

But while the theory which Loeb tried to support cannot 
be upheld (any more than the general osmotic theory of water 
absorption) he threw out with his rejected oedema views an 
experimental fact which is of permanent scientific value, and 
which, if it had been properly appreciated by pathologists and 
clinicians, would have spared us much of the late literature on 
this subject. I refer to his experiments carried out with the • 
intention of establishing the fact that the cause of oedema resides 
in the tissues. 

II 

THE CAUSE OF (EDEMA RESIDES IN THE TISSUES 

A simple experiment proves this. If one leg of an ordinary 
frog (Rana), a tree frog (Hyla) or a toad (Bufo) is ligated just 
above the knee as tightly as possible, so that the ligature shuts 
off not only the venous flow, but also the arterial, and the animal 
is then placed in sufficient distilled water to cover the legs, the 
ligated leg develops an intense oedema, while the unligated one 
remains normal. To explain this result recourse cannot be had 
to the pressure of any circulating liquids, for none such exists, 
and so all the conceptions of oedema which regard the pressure, per se, 
of circulating liquids, as one of the causes, or the chief cause, in the 
development of this condition, are robbed of their most fundamental 
support. ' 

The choice of animals for these experiments was not entirely 
a random one. It seemed desirable to deal with such in which 
there exists normally an outside source of water for the tissues, 
one separate from the ordinary blood or lymph current. Such 
conditions are satisfied in any of the amphibians. Nevertheless, 

1 Loeb's original paper discussing oedema appears in Pfluger's Arch., 
71, 457 (1898). His collected papers in English appear under the title, 
Studies in General Physiologie, I and II, Decennial Publications of the Uni- 
versity of Chicago, Chicago (1905). What is left of the original article 
appears on page 501, 



OEDEMA 



221 



an absorption of water may be obtained through the skin of all 
animals, for my toads developed just as intense cedemas of the 
leg as did the frogs, and it is a well-known fact that the bodies 
of dead land animals swell (become oedematous) if kept in 
water. 1 

The cedemas which these frogs and toads develop are in every 
way a counterpart of the most intense forms observed clinically. 
The tissues are boggy, pit on pressure and when incised allow 
the escape of fluid. 

The rate at which the oedema develops in the three types of 
animals is not the same. It develops and passes away most 
rapidly in tree toads (Hyla). For toads (Bufo) and ordinary 
frogs (Rana) the following holds: An oedema of the ligated leg 
is readily discernible at the end of eighteen hours, and is marked 
at the end of twenty-four. Within forty-eight hours the swelling 
approaches its maximum, and may at times be so great that the 
skin of the ligated leg is ruptured. This maximal swelling is 
usually maintained some two days, when it begins to 
diminish. 

The diminution in the size of the leg is at first merely due to 
loss of water, dependent upon changes in the tissues which we 
shall discuss later. But in the entire absence of a circulation 
the leg below the ligature cannot, of course, continue to live, and 
so anywhere from one to two weeks after the ligation, the skin 
peels and splits and the tissues below it become soft and disin- 
tegrate. This loss of substance becomes progressively greater 
until at the end of three to five weeks only a bony stump covered 
with tags of tissue may be left. 

A number of accessory phenomena are deserving of mention. 
Twenty-four to forty-eight hours after the ligature has been 
tied a number of small vesicles usually begin to develop upon the 
oedematous leg. They are found earliest and most commonly in 
the tissues of the web of the foot, but they may occur anywhere 
in the skin below the ligature. The small vesicles, which appear 
early, gradually increase in size until forty-eight to ninety-six 
hours after the ligature is tied they become great blebs, which 
in place of the original water-white or faintly straw-colored fluid 

1 It is needless to point out that the bloating of bodies in consequence of 
the development of gas through bacterial action in the gastro-intestinal tract 
or in the tissues proper is, of course, not referred to in this remark. 



222 



(EDEMA AND NEPHRITIS 



found in the vesicles, are likely to contain (especially in toads) 
a blood-stained serum. After these have persisted a day or two, 
they rupture and allow the escape of their contents. 

The color of the skin of the ligated legs also suffers change. 
Within twelve hours after the ligature is tied this is usually seen 
to fade somewhat, and to lose the luster of the healthy skin. At 
the end of forty-eight hours the color markings, characteristic 
of the particular species of frog under observation, are much 
blurred. Late in the experiment (in the second or third week), 
the ligated leg assumes the gray or grayish-black look of 
necrosis. 

What has been said is illustrated in Figs. 87, 88, 89, 90 and 91. 
Fig. 87 is a photograph of a frog (Rana), kept in a little water, 
forty-seven hours after a ligature has been tied as tightly as 
possible about the left leg. The increase in the size of this leg 
over the normal right is clearly apparent. Figs. 88 and 89 illus- 
trate the same fact in another frog treated the same way. The 
tense skin with the blurring of surface markings is easily noted 
in all three pictures. Later photographs of the frog of Fig. 87 
are shown in Figs, 90 and 91. These were taken ninety-five 
hours after the ligature was tied. Some small blisters which 
formed between the toes have increased in size to constitute the 
large bleb seen in the photographs. The oedema in the leg and 
foot generally is still evident. 

While these photographs show us that an oedema develops 
in a frog's leg even in the total absence of a circulation, they 
tell us nothing of the severity of these cedemas; in other words, 
simple inspection of the illustrations does not yield conclusive 
evidence that the cedemas are as severe as any ever observed 
clinically. To settle this a few experiments are given in which 
the cedematous legs were amputated at various periods after 
their ligation and their weight compared with that of the normal 
leg of the opposite side. 

Experiment 1. December, 1907. — One leg is ligated with silk 
just above the knee in each of four toads (Bufo), and they are placed 
in separate dishes, each containing enough distilled water (50 cc.) to 
cover the legs. The ligated legs are found visibly oedematous at the 
end of twenty hours. The toads are left in the dishes for fifty-four 
and one hundred and sixty-eight hours, when they are killed, and the 
two legs are amputated (the ligated one just above the ligature, the 
other at a corresponding point on the opposite leg), and weighed. 




Figure 87. 



224 



(EDEMA AND NEPHRITIS 



i 




Figure 88. 



(EDEMA 



225 




Figure 89. 



226 



(EDEMA AND NEPHRITIS 




Figure 90. 



(EDEMA 




I 

i 
i 



L 



Figure 91. 



228 



(EDEMA AND NEPHRITIS 



The difference in weight, with the gain on the part of the ligated leg, 
expressed in percentage of the weight of the unligated leg, is shown 
in the table. 

kav. t ak /Ligated, 0.436 (+26%) 
o4 hours, Toad A 0.346 (0%) 

ka*. t at> [Ligated. 0.371 (+25%) 
o4 hours, Toad B q.296 (0%) 

* /Ligated, 0.444 (+45%) 

o4 hours, Toad C | Unliga ted, 0.306 (0%) 

™ m ( Ligated, 2.152 (+82%) 
168 hours, Toad D ^ ^gated, 1.180 (0%) 

Experiment 2. March, 1908. — Ligatures are tied as tightly as pos- 
sible just above the knee about the left hind legs of six toads (Bufo). 
They are placed in finger bowls containing 100 cc. distilled water. After 
varying periods they are taken out, killed, and the weights of their hind 
legs compared as already outlined. The results are given in the table: 

- rp j \ f Ligated, 1.080 (+33%) 

4.30 hours, Toad A < T - e r 7 , n C1A ; nr -^ 
' \Lnligated, 0.810 (0%) 

T , D f Ligated, 3.350 (+58%) 
-30 hours, ToadB ^gated, 2 .120 (0%) 

oo m i. t j f Ligated, 4 . 137 ( +80%) 
28.00 hours, Toad C {^^ted, 2.295 (0%) 

, Q ~ ,-p. 'Ligated, 7.840 ( +56%) 

43.45 hours, Toad D { UnH gated, 5.020 (0%) 

r^onnT. t a i? / Ligated, 7.262 (+130%)? « 
53 . 00 hours, Toad E ( Un H gated , 3 . 152 (0%) 

10 , rri , ^ f Ligated, 7.160 (+23%) 

124. 4o hours, Toad F { Unligated , 5.810 (0%) 

1 The toes of the sound leg are missing. The oedematous leg is practically 
covered with large blebs. 

These experiments prove that the severest grades of oedema 
may develop in toads and frogs in the entire absence of a circula- 
tion. Their validity to do so has, however, been questioned. 
The objections raised come to this, that in spite of the ligature 
some sort of a blood or lymph circulation with its ever-adherent 
" pressure " still exists in the leg. One should, of course, be 
convinced that no ordinary circulation can continue through 
the soft tissues of the leg when it is remembered that the ligature 
is tied as tightly as possible about the leg at a point where 
musculature is practically lacking. The only other possibility 
for a circulation would have to be found through the lower end 
of the femur, and the tissues in and about the knee-joint, whereby 



(EDEMA 



229 



a connection between the thigh above, and the leg below, might 
be conceived to be continued. These objections are answered 
by two facts: (1) // the ligature is tied about one leg of a frog, 
and the animal is not kept in water, but in a dry vessel, the ligated 
leg dries up entirely, and this member is carried about in a mummified 
condition for as long as the experiment is continued. The rest 
of the frog dries out more slowly than the ligated leg. (2) If 
after ligating the leg the member is amputated and placed in a 
little distilled water, it shows the same series of changes as though 
it had been left united to the frog. We will find abundant evidence 
of this fact in experiments to be described later. Ocular 
demonstration of it may be found in Fig. 92. In this are 
shown anterior and posterior views of two frogs' (Rana) legs 
forty-nine hours after they had been ligated, amputated, and 
placed in distilled water. The spreading toes, bulging webs, 
and swollen leg muscles betray the oedema. Its severity is 
made apparent when it is stated that both legs have gained over 
50 per cent in weight. It would be difficult to conjure up the 
existence of any orthodox circulation in this experiment with 
amputated legs. 

Experiments 3 and 4 may serve in further illustration of 
what has been said. In these, tree toads were used. Similar 
experiments with frogs will be described later and need not be 
dealt with separately here. 

Experiment 3. December, 1907. — A ligature is passed about the 
left leg above the knee in each of two tree toads. The one toad is kept 
in a dry vessel, the other in one containing a little distilled water. 
Twenty hours later, oedema is well marked in the ligated leg of the frog 
kept in water, while that of the frog kept dry is already beginning to 
shrivel. At the end of fifty-eight and one-half hours the toads are 
killed, the legs amputated and weighed, with the following results: 

rr rp j a i i- a (Ligated, 0.071 (-38.8%) 
Tree Toad A, kept dry ( v ^ ig ^ d> n6 (0%) 

t t a T3 i * /Ligated, 0.279 (+78.8%) 

Tree Toad B, kept moist j ungated, . 156 (0%) 

Experiment 4. June, 1908. — Three tree toad legs are amputated 
close to the pelvis. The skin is pulled over the femoral stumps and 
ligated tightly. The legs are weighed and placed in separate finger 
bowls each containing 110 cc. distilled water. The first figure in each 
of the columns is the weight of the tree toad's leg at the beginning of 
the experiment. After each of the subsequent weighings is given in 



CFDEMA AXD NEPHRITIS 




A 



B 

Figure 92. 



OEDEMA 



231 



parentheses the percentage of increase in weight over the original 
weight of the muscle. 



Hours in the 
solution. 


110 cc. H2O. 


110 CC. H2O. 


110 cc. H2O. 





0.486 (0)% 


0.473 (0)% 


0.363 (0)% 


yj . o\j 


u . OOU -\- 10 . Z ) 


O ^40 (-1-14. 1 


O 41 7 ( 4-1 4 


1.30 


0.600 (+23.4) 


0.590 (+24.6) 


0.465 (+28.1) 


2.30 


0.630 (+29.6) 


0.620 (+31.0) 


0.498 (+37.2) 


4.30 


0.712 (+46.5) 


0.703 (+48.6) 


0.557 (+53.4) 


6.10 


0.795 (+63.5) 


0.770 (+62.8) 


0.620 (+72.7) 


17.35 


0.944 (+94.2)x 


0.799 ( +68. 9)x 


0.662 (+82.3)x 


22.25 


0.842 (+73.2) 


0.772 (+63.2) 


0.627 (+74.7) 


28.45 


0.780 (+60.5) 
d 


0.755 (+59.8) 
d 


0.598 (+64.7) 



d, d, represent opposite legs of the same toad, 
x. At this point the legs are found blistered. 



Fig. 93 is based upon the calculations contained in Experiment 
4, and represents graphically the course of water absorption 

100 1 1 1 1 1 1 1 




oi 1 1 1 1 ■ 1 

5 10 15 20 25 30 

Hours 

Figure 93. 



as observed in these three amputated tree toads' legs. The 
curves show that the initial increase in weight is followed later 
by a decrease. This corresponds with the ocular observations 
already detailed on the development of oedema in ligated legs 
left in situ. 



232 



(EDEMA AXD NEPHRITIS 



After what has been said it will not seem strange that these 
oedematous changes in a ligated leg occur in a toad or frog just 
as readily and rapidly when the animal has its central nervous 
system destroyed as when this is not done. If, however, the 
animal dies, the difference between the weights of the two legs 
does not develop. But this is not because the cedema does 
not develop in the ligated leg — it does just the same — but an 
equally intense absorption of water occurs in the other leg which 
through the death of the animal has been deprived of its circulation. 

These experiments already enable us to cast aside all those 
explanations of cedema which attribute its development to 
pressure changes per se of circulating liquids. The cause of oedema 
resides in the tissues themselves, and these become oedematous 
not because water is forced into them, but because changes take 
place in them whereby they are enabled to absorb water from any 
available source. In the case of the experiments on toads and frogs 
this available source of water is the water contained in the dishes 
in which the animals are kept. In clinical cases of oedema, it is 
found in the fluids which pass through or about a tissue. 

Ill 

ON THE NATURE AND CAUSE OF (EDEMA 

We are now in a position to attempt an analysis of the nature 
and the cause of cedema. In order to render clear the argument 
that follows and the purpose of each experiment, we will at 
once state our conclusion. A state of oedema is induced when- 
ever, in the presence of an adequate supply of water, the capacity 
of the colloids of the tissues for holding water is increased above that 
which we are pleased to call normal. Any agency capable under the 
conditions existing in the body, of thus increasing the hydration 
capacity of the tissue colloids constitutes a cause of oedema. The 
accumulation of acids within the tissues brought about either 
through their abnormal production, or through the inadequate 
removal of such as some consider normally produced in the tissues, 
is chiefly responsible for this increase in the hydration capacity 
of the colloids, though the possibility of explaining at least some of 
it through the production or accumulation of substances (of the 
type of urea, pyridin, certain amins, etc.) which can hydrate 



(EDEMA 



233 



colloids as can acids, or through the conversion of colloids having 
but little capacity for water into such as have a greater capacity 
must also be borne in mind. 

It was the purpose of Part Two in this volume to 
prove that in the colloids of the tissues and in their variable 
capacity for holding water we have an adequate explanation 
for the largest amounts of water ever held by tissues under phys- 
iological conditions or in states of excessive swelling (excessive 
turgor, plasmoptysis, cedema). We need now to discuss how 
the degree of hydration characteristic of normal cells may be 
so increased that they are judged cedematous. Of the several 
agencies active here we shall discuss in greatest detail, because 
we consider it most important, the question of an abnormal 
production and accumulation of acid in the involved tissues. 

Our proof for the truth of the general conclusion stated 
above will take three directions: 

1. An abnormal production or accumulation of acids, or con- 
ditions predisposing thereto, exist in all states in which we encoun- 
ter the development of an cedema. 

2. Conversely, any means by which is rendered possible the 
abnormal production or accumulation of acids in the tissues is 
accompanied by an cedema. 

3. The development of an cedema is antagonized by the 
same substances which decrease the capacity of hydrophilic 
colloids for holding water and is unaffected by substances which 
do not do this. 

We will consider these separately: 

1. An Abnormal Production or Accumulation of Acids or Condi- 
tions Predisposing Thereto Exist in all States in which We 
Encounter (Edema 

§ i 

We are especially prone to see states of cedema develop 
in conjunction with circulatory disturbances. Thus, when the 
function of the heart is sufficiently impaired an cedema which 
is more or less general affects the body. It is ordinarily said 
that because of the disturbance in the circulation an increased 
capillary pressure results, in consequence of which fluid is 



234 



(EDEMA AND NEPHRITIS 



squeezed into the tissues. And yet everyday clinical experi- 
ence shows that such reasoning is entirely wrong, for if we give 
our patient digitalis or some other heart " stimulant " which 
increases the blood pressure the oedema gets better, not worse. 
What we have said regarding a disturbance in the general circula- 
tion holds also for the local interferences with the circulation 
as through thrombosis, embolism, or ligation of an artery or 
vein supplying any part of the body. If a good collateral circula- 
tion exists, the thrombosis, embolism, or ligation may be entirely 
without effect, or if such a collateral circulation is gradually 
established the oedema may gradually pass away; but if neither 
of these is possible, then the oedema persists. 

j A patient tends to develop a general or a localized ozdema 
whenever an insufficient amount of arterialized blood is being pro- 
pelled through his tissues, and any general or local condition which 
produces such a state or aggravates an existing one, aggravates 
the oedema, and vice versa. This is why postural changes, 
rest in bed, drugs which increase the effectiveness of the heart's 
work, and measures which tend to restrict those physiological 
functions which we know normally to be followed by an increased 
demand for blood all help to improve an oedema, while the 
reverse does the opposite. 

But how does insufficient flow of normal blood through a 
tissue lead to an oedema? Is such accompanied by an abnormal 
production or accumulation of acid? As already stated, this 
is what we need and know from our previous experiments to be 
potent in increasing the capacity of the tissue colloids for water. 
That this is the case is a well-known and long-established fact. 
When the blood is not carried away from a tissue at its normal 
rate there tends to accumulate in it and in the tissues drained 
by it the carbonic acid which is constantly being produced 
in our cells. It is this carbonic acid which under normal circum- 
stances accounts for the swelling of the red and white blood 
corpuscles whenever the arterial blood changes to venous, 1 
and this tendency is greatly heightened when the normal blood 
is replaced by the highly venous blood encountered in circulatory 
disturbances. What happens in the cells of the blood happens 
also in the tissues and cells drained by that blood. They all tend 

1 See the experiments of Hamburger, von Limbeck, Gryns, Eijkman, 

etc. 



(EDEMA 



235 



to swell just as do fibrin flakes in water when the carbonic acid 
tension in it is increased. The observation of Strassburg and 
Ewald that the carbonic acid content of oedema fluids and of 
tissues deprived of a circulation runs very high is therefore one 
of the factors to be considered in trying to find a cause for the 
increased capacity of the tissues for holding water in states of dis- 
turbed circulation. 

There exists, however, a second and more powerful factor 
which leads to an abnormal acid production when the circulation 
is disturbed. This is brought about through the inadequate 
supply of oxygen to the affected parts. As first proved through 
the striking experiments of Trasaburo Araki, 1 dogs, rabbits, 
and frogs excrete lactic acid in their urine in addition to various 
other abnormal substances whenever subjected to oxygen want 
by any means whatsoever. Under ordinary circumstances lac- 
tic acid is not found in the urine, but let the oxygen supply 
to these animals be sufficiently reduced (through confinement 
in a closed box, through carbon monoxid poisoning, or through 
the injection of curare, amyl nitrite, or cocain, and the acid 
appears. Such acid is also found in human beings when through 
accident or disease they are compelled to suffer from oxygen 
want. Lactic acid is not the only acid that may be or is produced 
under such circumstances. E. Mendel 2 found the phosphoric 
acid content of the urine increased after epileptic seizures and 
in apoplexy, and F. Hoppe-Seyler 3 found various cedema 
fluids to contain valerianic, succinic, and butyric acids, besides 
lactic. 

The lactic acid found in the urine in conditions associated 
with a lack of oxygen is produced in the tissues, enters the blood, 
and is excreted by the kidneys. This has been proved by 
Araki's later work and through Hermann Zillessen's 4 experi- 
ments. Zillessen found that when the oxygen supply to a 
muscle or to the liver is shut off for a variable number of hours 
through ligation of the arteries supplying these parts, an increased 
production of lactic acid occurs. If the ligature is loosened and 
the first blood returning from the oxygen-starved tissues is 

1 Trasaburo Araki: Zeitschr. f. physiol. Chemie, 15, 335 and 546 (1891) ; 
ibid., 19, 422 (1894). 

2 E. Mendel: Arch, f . Psychiatrie u. Nervenkrankheiten, 3, 636. 

3 F. Hoppe-Seyler: Zeitschr. f. physiol. Chemie, 19, 476 (1894). 

4 Hermann Zillessen: Zeitschr. f. physiol. Chemie, 15, 387 (1891). 



236 



(EDEMA AND NEPHRITIS 



analyzed, this is found to be particularly rich in lactic acid, 
and if the blood is titrated, it is found to have a diminished 
capacity for neutralizing a standard oxalic acid solution. 1 

In consequence of circulatory disturbances, whether^ general 
or local, an abnormal production and accumulation of carbonic, 
lactic and other acids occurs which increases the hydration capacity 
of the colloids of the involved tissues, because of which they then 
suck water out of the blood and lymph streams bathing them, 

§ 2 

In place of interfering mechanically with the circulation we 
may make the tissues suffer from a lack of oxygen, and thus from 
an abnormal production and accumulation of acid, by interfer- 
ence with the normal oxygen-carrying power of the blood. We 
find in this a ready explanation of the oedemas so frequently 
noted in the severe anemias, no matter what their cause. It 
is of interest, therefore, that Felix Hopfe-Seyler 2 was able 
to isolate lactic acid from the urine in two cases of severe anemia. 
As additional evidence in this direction may be cited R. von 
Jaksch's 3 findings, amply verified by subsequent workers, 
that the blood shows a distinctly diminished power of neutraliz- 
ing acid in pernicious anemia, leukemia, and chlorosis. That 
this decrease in the ability to neutralize acids really means 
that an abnormal production of acids has occurred in the tissues 
of the anemic individual, is evident not only from the work of 
Araki and Zillessen already cited, but from von Jaksch's 
own finding that in carbon monoxid poisoning in which the ab- 
normal presence of lactic acid in the urine has been indisputably 
shown by Araki, there also exists a distinct decrease in the 
normal capacity of the blood to neutralize acids. 

§ 3 

An oedema, often of a severe grade, is the almost constant 
accompaniment of various states of inanition. It is observed 

1 Araki, Zillessen and most of the earlier observers speak of a "decreased 
alkalinity " of the blood. Because modern physico-chemical conceptions 
have changed our old notions of what constitutes alkalinity, it is best to 
state the experimental findings of these authors as above. 

2 Felix Hoppe-Seyler: Zeitschr. f. physiol. Chemie, 19, 473 (1894). 

3 R. von Jaksch: Klinische Diagnostik, 5th Ed., Berlin (1901). 



(EDEMA 



237 



not only in starvation, but in the various forms of scurvy that 
are observed clinically, and the experimental types that may 
be induced in animals. What evidence have we for the abnormal 
production or accumulation of acids in all these conditions? 
We are, first, not without clinical evidence. The observations 
on human beings undergoing a voluntary fast all agree in showing 
that the urine grows progressively more acid with each day 
of starvation. The only exception to this rule was noted by 
Luigi Luciani 1 in his study of Succi during a thirty days' 
fast. For the first six days of Succi's fasting there was a gradual 
increase in the acidity of the urine; for the rest of the period 
it remained very high in spite of the fact that he consumed large 
amounts of alkaline mineral water. 2 A. E. Wright 3 has 
made a further observation of interest. He noted a diminution 
in the capacity of the blood to neutralize acid in seven cases of 
scurvy. 

Yet more convincing are the experimental studies on starv- 
ing animals. The normally acid urine of the carnivora becomes 
more intensely so with progressive starvation, and in herbivora, 
the normally alkaline urine becomes highly acid. The same 
occurs if animals (especially herbivora) are fed an exclusive 
diet of any sort. An exclusive oat diet, which is high in acid 
salts and low in calcium, is quickly fatal. H. Weiske 4 found 
that when certain mineral salts, especially calcium salts (which 
are peculiarly powerful in neutralizing the effects of acid), are 
added to the pure oat diet the animal fares better. A thorough 
study of starvation and such one-sided diets, rich in acids and 
poor in calcium, has been made by Axtel Holst and Theodor 
Frolich 5 . They describe as constant findings in their experi- 
ments the occurrence of cedema. " A pronounced universal 
anasarca " was noted in all the starved animals, while those fed 
exclusively on oats, barley, wheat, or some of their derivatives 
showed various degrees of cedema up to such universal anasarcas. 

1 Luigi Luciani: Das Hungern, 164, Hamburg und Leipzig (1890). 

2 Succi's fasting period was long enough to have allowed of the develop- 
ment of an cedema, and yet none is noted in Luciani' s account of the case. 
I attribute this to the beneficent effects of the mineral water he consumed. 
See the effects of alkali and salts on cedematous states as given below. 

3 A. E. Wright: Lancet, 2 (1900). 

4 H. Weiske: Zeitschr. f. Biologie, 31, 421 (1895). 

5 A. Holst and T. Frolich: Journal of Hygiene, 7, 634 (1907). 



238 



(EDEMA AND NEPHRITIS 



Close scrutiny of Holst and Frolich's experiments would seem 
to indicate that the more liberal the variety of the salts in the 
diets, the less the tendency to observe an cedema. 

§4 

(Edema is a not uncommon accompaniment of fever. In 
some fevers it constitutes a symptom so marked that it is looked 
for clinically; in others, the increased amount of water held by 
the patient is clearly indicated by his increase in weight and his 
failure to secrete an amount of water through kidneys, lungs, 
skin and bowel, the equivalent of that ingested. With remis- 
sion or discontinuance of the fever there has been noted by the 
most careful observers an increase in the output of water by all 
the water-secreting organs above the amount ingested. 

It is not to be assumed, of course, that the fever, per se, is 
the cause of the cedema. It may contribute toward this end, 
however, for certain proteins absorb more water at a higher 
temperature than at a lower one. A highly acid urine is char- 
acteristic of fevers of the most varied kinds, and von Jaksch 
found a constant diminution in the neutralizing power of the 
blood for acids. As to the cause for this acid production we 
are still in the dark; it can be the indirect result of toxic changes 
induced in organs of the circulation (for example, the heart), 
but in major part it is consequent upon the action of the poison- 
ous (fever-producing) substances on the tissues generally. We 
need only call to mind the great inhibition of various oxidations 
occurring normally in the body and necessary for the continua- 
tion of life that various bacterial and animal toxins produce. 
Any classification of the cedemas is necessarily an arbitrary one, 
and what I have called here the cedema of fever must ultimately, no 
doubt, fall into the group of the general toxic cedemas. 

§ 5 

(Edema is an almost constant accompaniment of certain 
types of nephritis. We cannot, of course, accept the belief that 
the cedema associated with diseases of the kidneys is dependent 
upon the increased blood pressure which is found in some cases 
of nephritis. As a matter of fact, the most intense cedemas 
are encountered in the so-called parenchymatous types of neph- 



(EDEMA 



239 



ritis, the very ones in which we are least likely to note a rise in 
blood pressure. Nor is it true, as ordinarily taught, that the 
oedema is consequent upon the kidney disease. It is as primary 
as the kidney disease itself, as we shall see later. 1 

As evidence of an abnormal production or storage of acids in 
nephritis we note that the urine of nephritics is generally acid 
in reaction, and often highly so. More convincing still is von 
Jaksch's finding that the " alkalinity " (acid-combining power) 
of the blood is constantly and markedly decreased in the severer 
nephritides. This existence of a constantly and highly acid 
urine, and a lowered capacity of the blood-to combine with acids, 
may at first sight seem unconvincing evidence in favor of the 
abnormal production of acids in this condition and in certain 
others associated with oedema that we have discussed, but to 
value it correctly we need only remember that in the severest 
experimental intoxications with acids, those in which large amounts 
of acids of known strength are introduced into the stomach, 
peritoneal cavity, blood, or subcutaneously, no more evidence 
of the acid intoxication can be found than just such an increased 
acidity of the urine and decreased acid-capacity of the blood. 
Furthermore, a change in degree of acidity to which our ordinary 
indicators respond only indistinctly, shows itself by marked 
differences in the swelling of colloids. 

We learn from Araki and Zillessen's observations that 
an abnormal production of lactic and other acids occurs in animals 
whenever they are subjected to want of oxygen by any means 
whatsoever. In their experiments they used methods which 
varied from such as act through direct interference with the 
oxygen supply to the animal (compression of trachea) to such as 
owe their effect to an action upon the oxidizing ferments of the 
■tissues themselves (hydrocyanic acid). It is of interest, there- 
fore, to note that A. Jolles, Oppenheim, 2 M. C. Winternitz 
and J. C. Meloy, 3 have found substances present in the blood 
of nephritics which interfere with at least some of the oxidation 
phenomena which we know to be necessary for the proper con- 
tinuance of life. 

1 See page 491. 

2 Jolles and Oppenheim: Munchener med. Wochenschr., 47, 2083 
(1904). 

3 M. C. Winternitz and J. C. Meloy: Jour. Exp. Med., 10, 759 (1908); 
Winternitz: ibid., 11, 200 (1909). 



240 



(EDEMA AND NEPHRITIS 



§ 6 

We can advantageously consider next what may be called 
the oedema of the dead. After death, as is well known, the acid 
content of the tissues rises rapidly. In fact it soon reaches such 
a point that our commonest and coarsest indicators suffice to 
show its presence. For the most part the acid formed is lactic 
acid. It matters little what we assume to be either the origin 
of this acid or the exact chemical change whereby it is produced. 
The presence of so much acid in the tissues gives us all the con- 
ditions necessary for the development of the most intense grades 
of oedema if only water is available. Since our conception of 
oedema possesses no " vitalistic " attributes, we are not surprised 
to find that a dead body develops an oedema quite as readily, if 
not more readily, than a living one. This explains the " oedema " 
which develops in the dead when they lie in water, and why the 
intravenous injection of a physiological salt solution which 
does not lead to an oedema in a living animal is promptly 
followed by such if done upon the dead. A living frog kept 
up to its neck in distilled water for several days shows a varia- 
tion of less than 3 per cent in weight; the same frog after being 
killed gains progressively until, at the end of sixty hours, it has 
absorbed from 30 to 60 per cent of its original weight. 

§ 7 

It is self-evident that what has been said regarding the general 
oedemas holds also for the local oedemas. There is no imaginable 
difference between the cause for a general oedema, the result of 
a leaking heart valve, and the cause for the local oedema observed 
in an infarcted area, except that if the infarction is due to plugging 
of an end artery with an embolus, no increased blood pressure 
is available for its explanation. But this is not needed, for 
through the defective blood flow through the part an abnormal 
production and accumulation of acid occurs in the infarcted 
area which increases the capacity of the tissue colloids for water, 
and so they suck it up from their surroundings as does a dead 
body from the water in which it lies. For this reason the infarct 
in its earlier history always shows itself as the familiar swollen, 
firm pyramidal mass, which stands out prominently from the 



(EDEMA 



241 



surrounding tissues. The subsequent decrease in size is due to a 
' combination of changes (coagulation, autodigestion, solution) 
identical with those observed in tissues laid in weak acid solutions. 

The gangrenes present the same problem as the local circulatory 
disturbances. Their chief interest to us lies in the question of 
whether they will be moist or dry. If water is furnished the 
dead or dying tissues, either from without or through the blood 
or lymph circulation, they swell and a moist gangrene results; 
if this does not happen, we have a dry gangrene. In a gangrene 
due to closure of a vein, a moist gangrene is therefore to be 
expected, while a gangrene due to obstruction of an artery is 
more likely to be dry. 

The local cedemas following the bites or stings of insects have a 
special interest. In quite a number of these the sting carries 
formic or other acids into the tissues. Here we have a direct 
etiological factor for the production of the local oedema. In 
others, poisons are injected which have a well-marked reducing 
power. By this means a local group of cells are placed in a state 
of lack of oxygen through chemical means. It is worthy of note 
that originally and during the period of greatest swelling such 
insect stings are white, and not until later do they become red. 
The increased blood flow so necessary in most explanations of 
these local cedemas does not occur until the oedema ,has begun 
to subside. Instead of the blood circulation determining the oedema 
the oedema determines whether the circulation shall continue through 
the affected part or not. 

This explanation of the nature and cause of the local cedemas 
can be further tested. The cedematous wheals following bites 
or stings can be mimicked perfectly with a gelatin plate and a 
little acid. If with a fine hypodermic needle a little formic 
acid is stabbed into a gelatin plate, and the whole is then 
laid into water, an urtica rial-like wheal develops about each spot 
pricked with the needle, which in shape and in rate of develop- 
ment is not unlike those which follow the bite of an insect or the 
introduction of a formic acid laden needle into the skin. This is 
illustrated in Figs. 94 and 95. In Fig. 94 the surface of a 6 per 
cent gelatin has been touched in different spots with a needle 
dipped in formic acid, while in Fig. 95 the prickings have been 
carried out in a design. The swelling of the gelatin about each 
of the points touched with the needle is readily apparent. 



242 



(EDEMA AND NEPHRITIS 




Figure 94. 



In Fig. 96 are shown some wheals which developed acci- 
dentally on the surface of some of my gelatin discs. The par- 
ticular disc pictured had 
lain for thirteen days in 
n/20 hydrochloric acid. 
The hyaline gelatin does 
not photograph easily, 
and so the figure does 
not indicate how clearly 
these wheals imitate such 
as are observed clinic- 
ally. Those shown here 
are due to local infections 
of the gelatin with a 
mold. In place of the 
perfectly smooth surfaces 
which these gelatin discs 
show ordinarily, we see 
them here studded with 
small mounds indicative 
of irregularities in the absorption of water. The cause for these 
local swellings may be a twofold one. As the mold developed 
while these discs were lying 
in dilute acid solutions, I 
question whether an addi- 
tional local production of 
acid (of which the molds 
are capable) gave rise to 
the local swellings. The 
affected spots are softer 
than the surrounding gela- 
tin, and later became al- 
most liquid. I think, in 
consequence, that the gela- 
tin suffers a partial diges- 
tion under the influence 
of proteolytic ferments 
manufactured by the mold 

in the affected spots. Such a partially digested gelatin corresponds 
with the Beta-gelatin of Traube, which we know from Wolf- 




Figure 95. 



GEDEMA 



243 



gang Ostwald's 1 experiments to be capable of a distinctly 
greater swelling than ordinary gelatin. 

In passing let it be noted that this simple observation teaches 
how a chemical change in the colloid itself, in this case induced 
through a ferment — just such a change as might occur in living 
matter — may affect its capacity for holding water. This is a 




Figure 96. 



fact not without biological significance in this problem of the 
ways and means by which a tissue regulates its water content, 
as we shall discuss in greater detail later. 

2. Any Means by which an Abnormal Production or Accumulation 
of Acid in a Tissue May be Brought about is a Means of 
Producing an (Edema 

We now pass to the second link in our chain of evidence. 
Any condition which makes for the production of acid in the tissues 
leads to the development of an oedema if a source of water is available. 

§ i 

The quickest way to put the tissues of an animal into a con- 
dition that permits of the development of acids in them is to 
1 Wolfgang Ostwald: Pfliiger's Arch., 109, 277 (1905). 



244 



OEDEMA AND NEPHRITIS 



kill the animal. The fact does not surprise us, therefore, that 
an oedema develops with greater ease in a dead animal than 
in a living one. If a living frog is kept up to its neck in dis- 
tilled water it suffers little variation in weight. A change in 
weight of 3 per cent covers the extremes. But let the frog be 
killed and be kept similarly covered with water and a progressive 
rise in weight at once sets in. This is readily apparent from the 
following experiments: 

Experiment 5. January 3, 1909. — Three frogs which had suffered 
no appreciable change in weight after residence for several days in 
distilled water, had the urine expressed from their bladders, were killed, 
weighed and hung into jars containing distilled water. The original 
weights of the freshly killed frogs were as follows: 

49.5 34.3 39.2 

After the designated number of hours in distilled water the weights 
changed to the following. In parentheses after each weighing is given 
the percentage of increase in weight (water absorption) as calculated 
in terms of the original weights of the frogs : 



Hours. 


% 


% 


% 


10.15 


54.8 ( + 10.7) 


39.8 ( + 16.0) 


43.2 ( + 10.2) 


22.00 


57.9 ( + 17.7) 


42.2 (+23.0) 


45.0 ( + 14.7) 


33.15 


59.1 (+19.4) 


42.9 (+25.0) 


46.8 (+19.3) 


52.15 


63.0 (+27.2) 


46.0 (+34.1) 


49.8 (+27.2) 


74.00 


69.5 (+40.4) 


49.2 (+43.4) 


55.5 (+41.5) 



It is not necessary that the entire body of the frog be covered 
with water in order to allow such an oedema of the dead to develop. 
The dead body need only be in contact somewhere with a source 
of water. In the following experiment only a fraction of the 
bodies of the dead animals was immersed in water. 



Experiment 6. At 5 p.m., July 19, 1909, five frogs are killed and 
placed in separate jars, each containing a few cubic centimeters of 
water. The original weights of the frogs are as follows : 

40.0 38.5 35.0 30.5 28.0 

Nineteen hours later the frogs have gained in weight thus : 

55.5(+38.7%) 48.6(+26.2%) 46.0(+31.4%)39.5(+29.4%)36.5(+30.3%) 



(EDEMA 



245 



§2 

But we possess subtler methods of producing abnormal 
amounts of acids in the tissues than by killing our animals. 
We can use any one of a long series of poisons. I chose those 
which Araki used in his experiments on the effects of lack of 
oxygen. The introduction of these poisons into the bodies of 
warm or cold-blooded animals he found to be always followed 
by the production of excessive amounts of various acids (par- 
ticularly lactic acid) in the tissues. In a series of experiments 
made with Gertrude Moore, we found that the injection 
into the dorsal lymph sac of a frog of any of the poisons used by 
Araki is followed by an oedema. Frogs poisoned with morphin, 
strychnin, cocain, arsenic, or uranyl nitrate all absorb amounts 
of water which run from 15 to 60 per cent of the normal weight 
of the frog. A frog that has gained even 15 per cent in weight is 
decidedly cedematous. The oedema in all these cases begins 
to develop within a few hours after the poison is injected, and 
becomes progressively worse for twenty-four to seventy-two 
hours. The severer the intoxication the greater the oedema. 
If the amounts of poison injected have not been too large, and the 
animal is given a chance to eliminate it by renewing frequently 
the water in which the frog is kept, its oedema may be made to 
disappear entirely, and the animal come out none the worse 
for its experience at the end of three to six days. 

The following experiments may serve to illustrate what has 
been said: 

Experiment 7. Morphin (Edema. — A series of frogs which have 
been Jtept in distilled water for several days, have the urine expressed 
from their bladders, are weighed, injected with various amounts of 
morphin into the dorsal lymph sac and kept in separate jars contain- 
ing enough water to cover the legs (100 cc). The changes in weight 
are indicated in the table. The first figure in each of the columns shows 
the original weight of the frog. Above it is indicated the amount and 
form of morphin injected, 



246 



(EDEMA AND NEPHRITIS 



Hours. 


0.02 gram 
morph. 
hydroch. 


0.02 gram 
morph. 
hydroch. 


0.02 gram 

morph. 
hydroch. 


0.02 gram 
morph. 
hydroch. 




7.00 
10.15 
22.00 
26.00 
33.15 
47.30 
52.15 
74.00 
127.00 


% 

36.9(0) 


% 

37.8(0) 


% 

35.7(0) 


%. 

41.3(0) 
46.0 (+11.3) 

44.5(+ 7.7) 
43.5 (+ 5.2) 


40.2(+8.9) 
39.0 (+5.6) 


43.1 (+14.0) 
43.1 ( + 14.0) 


43.2 (+21.0) 
41.0 ( + 14.9) 


39.0 (+5.6) 


41.1 (+ 8.1) 


41.0 ( + 14.9) 


38.8 (+5.0) 
37.0 (+0.3) 
36.8 (-0.3) 


39.8 (+ 5.3) 
37. 5(- 0.8) 


41.0(+14.9) 
38.5 (+ 7.8) 
38.0(+ 6.4) 


A second series similarly treated gives the following result : 


Hours. 


0.04 gram 
morph. hydroch. 


0.08 gram 
morph. hydroch. 


0.05 gram 
morph. sulph. 


0.037 gram 
morph. sulph. 




3.30 
7.00 
18.00 
22.00 
26.00 
47.30 
90.30 


% 

42.7(0) 


% 

62.0(0) 


% 

48.7(0) 
50.7 (+ 4.1) 

58.0 (+19.0) 
59.0 (+21.0) 
Dying 


% 

40.2(0) 
45.5 (+13.1) 

53.5 (+33.0) 
Dead 


48.4 (+13.3) 


71.9 (+15.9) 


49.0 (+14.8) 
45.0(+ 5.4) 
45.0(+ 5.4) 


76.2 (+22.9) 
70.5 (+13.7) 
70.2 (+13.2) 

Still in strychnin- 
like spasms. 



Experiment 8. Arsenic (Edema. — Three frogs which have been 
kept in distilled water for four days have the urine expressed from 
their bladders, are weighed, and injected with the indicated amounts 
of Fowler's solution. The following table of weights is self-explanatory: 



Hours. 


0.25 cc. Fowler's 
solution. 


0.187 cc. Fowler's solution. 


0.125 cc Fowler's 
solution. 




% 


% 


% 





45.0(0) 


40.0(0) 


38.9(0) 


6.15 


50.0 (+11.1) 


47.3 (+18.2) 


39.0(+ 0.2) 


18.15 


Dead 


54.0 (+35.0) 


43.0 ( + 10.5) 


24.15 




57.0 (+42. 5) just died 


43.0 ( + 10.5) 



Experiment 9. Uranium (Edema. — Six frogs are injected with 
the indicated amounts of uranyl nitrate and placed in separate glass 



(EDEMA 



247 



jars each containing 100 cc. distilled water. The variations in weight 
are easily understood from the following table: 



Hours. 


0.24 gram. 


0-24 gram. 


0.2 gram. 




% 


% 


% 





52.3 (0) 


52.1(0) 


51.5(0) 


17.00 


58.0 ( + 10.9) 


59.5 ( + 14.2) 


61.8 (+20.0) 


22.30 


61.0 ( + 16.6) 


62.2 ( + 19.3) 


65.8 (+27.7) 


29.30 


64.0 (+22.3) 


66.5 (+27.6) 


70.5 (+36.9) 


45.30 


66.7 (+27.5) 


71.5 (+37.2) 


75.2 (+46.0) 


53.45 


68.0](+30.0) 


75.5 (+44.9) 


79.5 (+54.3) 


71.00 


Killed 


77.5 (+48.7) 


83.0 (+61.1) 


78.00 




Dead 


Dead 



Hours. 


0.2 gram. 


0.16 gram. 


0.16 gram. 




• % 


% 


% 





51.3(0) 


41.0(0) 


37.8(0) 


17.00 


61.2(+19.3) 


52.2(+26.8) 


47.5(+25.7) 


22.30 


63.3(+23.4) 


55.8(+36.1) 


48.3(+27.7 


29.30 


64.5(+25.7) 


61.5(+50.0) 


52.0(+37.6) 


45.30 


65.0(+26.7) 


65.5(^-59.7) 


53.8(+42.3) 


53.45 


69.0(+34.5) 


Dead 


57.0(+50.7) 


71.00 


69.0 (+34.5) 




58.0(+53.4) 


78.00 


71.0(+38.4) 




Dead 




Killed 







In another series of five frogs several injections of uranyl nitrate 
are made into the dorsal lymph sacs, as indicated below, and with the 
following results : 



Hours. 


0.04 gram. 


0.04 gram. 


0.03 gram. 




20.00 


% 

51.3(0) 
55.5(+ 8.2) 


% 

53.2(0) 
55.3(+ 3.9) 


'% 

46.2(0) 
48.0(+ 3.9) 


25.00 
32.30 


Uranyl nitrate 
0.08 gram. 

56.5 (+10.1) 
59.5( + 15.9) 


0.08 gram. 
54.0(+ 1.5) 

55.0(+ 3.4) 


0.06 gram. 

47.5(+ 2.8) 
49.0(+ 6.0) 


47.30 
53.00 
67.00 
71.30 
77.00 


Uranyl nitrate 
0.3 gram. 

61.0( + 18.9) 
66.0(+28.6) 
71.0 (+38.4) 
Killed 


0.24 gram. 
54.0(+ 1.5) 
58.5(+ 9.9) 
67.0(+25.9) 
Killed 


0.2 gram. 
50.0(+ 8.2) 

54.5(+17.9) 
63.0(+36.3) 
64.5(+39.6) 
Dead 







248 



(EDEMA AND NEPHRITIS 



Hours. 


0.03 gram. 


0.02 gram. 




% 


% 





45.5(0) 


38.0(0) 


20.00 


48.5(+ 6.6) 


41.0(+ 7.9) 




Uranyl nitrate 






0.06 gram. 


0.04 gram. 


25.00 


48 5 (_l a a) 




32 30 


50 C4- 9 9) 






Uranyl nitrate 






0.16 gram. 


0.08 gram. 


A 1 OA 
4/ . OU 


pa o / i ii n\ 
oU . o ( + 1 1 . U) 


39 . 5 ( + 3.9) 


tro fin 

oo . UU 


CO T / 1 1 O A\ 

oo.V ( + 18. U) 


41.5 (+ 9.2) 


Cf A A 

D7.UU 


oU.O (+31 .8) 


45.0 (+18.4) 


T1 OA 

71 . oU 


ol.o (+00.U) 


43.0 (+13. 1) 


77 . UU 


do .1 (+38.9) 


42.2 (+11 .0) 


oc on 
5o . oU 


d C O / 1 A A Cl\ 

DO. 8 (+44.D) 


41 .5 (+ 9.2) 


97.00 


68.5 (+50.5) 


42.0(+10.5) 


115.00 


77.5 (+70.3) 


" 45.5(+19.7) 


120.00 


Dead 


45.5(+19.7) 


126.30 




45.0(+18.4) 


138.30 




48.0(+26.3) 


143.00 




49.5(+30.2) 






2 days later, dead. 



Of these chemical cedemas, as we may call them for short, 
we shall have more to say later. Here we would only point 
out that we find - in the list of poisons enumerated above, heart 
poisons, kidney poisons, nerve poisons, poisons that increase 
or decrease blood pressure, that increase or decrease lymph 
flow, that injure blood vessel walls, or have not been proved to 
do so, etc. Does not this simple fact first of all, seriously ques- 
tion every theory of oedema that would establish any one or all 
of these conditions as the primary cause of all cedemas? Second, 
these chemical cedemas have interesting clinical parallels. 
The pufhness of the eyelids, the thirst, the diminished urinary 
output when arsenic is pushed to the physiological limit clinically 
is but the counterpart of the oedema observed in frogs; and the 
same is true of poisoning by certain other metals. Similarly, 
the thirst after the administration of morphin, chloroform, 
ether or alcohol (save in small amounts), the fall in urinary 
secretion, the increase in the weight of the individual, and the 
apparent signs of oedema are again but what we observed in 
frogs. All these substances make for a lack of oxygen and an ab- 



(EDEMA 



249 



normal production of acids in the tissues. In major part, their 
effects are therefore to be explained through this action upon the 
tissues of the whole body. The body tissues become oedematous, and 
the thirst, the fall in urinary secretion, etc., are secondary to this, 
as we shall see in greater detail later. 

3. Those Conditions which are Capable of Decreasing the Hy- 
dration of (Protein) Colloids Decrease (Edema, while Those 
Unable to do so do not Affect It. 

In discussing the absorption of water by fibrin and gelatin 
we found that acids (and various other substances) increase the 
amount of water that may be thus absorbed, and the previous 
paragraphs have tried to show that oedema represents in the 
tissues a similar excessive hydration of certain colloids, also 
induced through the presence of abnormal amounts of acids 
(and certain other similarly acting substances). But in discuss- 
ing the excessive absorption of water by protein colloids we 
noted that such could be reduced by various means. Thus, 
the great hydration induced through acids could be counter- 
acted by salts of various kinds. In this simple observation 
resides a method of testing the validity of the colloid-chemical 
theory of oedema. Clearly, the same conditions which have been 
found effective in reducing the swelling of fibrin and gelatin in 
acid solutions should also be found to counteract the develop- 
ment of oedema. The following experimental observations show 
this to be true, and thus furnish a scientific foundation for a 
therapy of oedema. We became familiar above with the fact 
that a circulation is unnecessary for the development of most 
intense grades of oedema. We found that frogs' legs which had 
been ligated, cut from the body, and placed in a little water, 
developed an oedema which mimics in every way the worst 
types observed clinically. We will use the oedemas developed 
in this way in amputated frogs' legs as one type upon which 
to analyze further the nature of the phenomenon. 

(a and b) It will first be well to get some conception of the 
rate of water absorption (rate of oedema development) in such 
frogs' (Rana) legs. Fig. 97 has been introduced for this pur- 
pose. The preparations for the experiments were obtained by 
throwing a loose ligature about the hind legs of frogs just above 



250 



(EDEMA AND NEPHRITIS 



the knee and amputating them, provision being made for a cuff 
of skin which could be pulled over the femoral stump before the 
ligature was finally drawn taut. In this way any leakage of 




+ 



absorbed water through the cut end of muscle, tendons, or bone 
at the point of amputation was avoided. 

The steady increase in weight of the amputated frogs' legs 
is readily apparent from the figure and from Table LXXIX, which 
contains the experimental data. The increase in weight does 
not go on indefinitely. It not only ceases after a time, but an 



(EDEMA 



251 



actual loss of water ensues. We noted the same to be true in the 
experiments on muscle. The cause for this secondary drop 
is not yet clear. An actual loss of muscle substance through 
" solution " in the surrounding medium plays a partial role. 
I imagined that autolytic changes whereby the hydrophilic 
muscle colloids are broken down into substances not colloid in 
character might account for some of the subsequent loss. While 
this may play a role, experiment seems to indicate that it cannot 
be a great one. A series of tree-toad legs (muscles only) which I 
prepared aseptically and allowed to remain at body temperature 
in a moist chamber for various periods of time showed even at the 
end of a week the same absorption curve that the fresh muscle 
shows. I have come to conclude, in consequence, that the sec- 
ondary loss of water occurs after the acid formed in the muscle has 

TABLE LXXIX 



Frogs' Legs 



Hours in the 
solution. 


110 cc. H 2 0. 


110 cc. H 2 0. 


110 cc. H2O. 




1.45 
6.00 
18.25 
42.30 
51.45 
68.15 
76.45 
90.30 
124.45 


% 

3.66 (0) 
3.84 (+ 4.9) 
4.00(+ 9.3) 
4.52 (+23.4) 
5.33 (+45.6) 
5.52 (+50.8) 
5.49 (+50.0) 
5.56 (+51.9) 
5.64 (+54.1) 
4.96 (+35.5) 
(a) 
I 


% 

3.34 (0) 
3.56(+ 6.5) 

3.77 (+12.8) 
4.22 (+26.3) 
5.03 (+50.6) 
5.22 (+56.3) 
5.34 (+59.8) 
5.39 (+61.3) 
5.32 (+59.3) 

4.78 (+43.1) 
(a) 

II 


% 

3.01 (0) 
3.24 (+ 7.6) 
3.38 (+12.2) 

3.83 (+27.2) 
4.60 (+52.8) 

4.84 (+60.8) 
4.98 (+65.4) 
4.86 (+61.4) 
4.84 (+60.8) 
4.54 (+50.8) 

(b) 
III 


Hours in the 
solution. 


110 cc. H 2 0. 


110 cc. H2O. 


110 cc. H 2 0. 




1.45 
6.00 
18.25 
42.30 
51.45 
68.15 
76.45 
90.30 
124.45 


% 

2.925 (0) 
3.09 (+ 5.6) 
3.28 (+12.1) 
3.73 (+27.5) 
4.55 (+55.5) 
4.84 (+65.4) 
5.17 (+76.7) 
4.99 (+70.6) 
5.00 (+70.9) 
4.08 (+39.4) 

(b) 

IV 


% 

3.555 (0) 
3.82(+ 7.4) 
4.06 (+14.2) 
4.59 (+29.1) 
5.55 (+56.1) 
5.76 (+62.0) 
5.75 (+61.7)] 
5.80 (+63.1) 
5.87 (+65.1) 
5.17 (+45.4) 

(c) 

V 


% 

3 . 145 (0) 
3.31 (+ 8.4) 
3:53 (+12.5) 
4.01 (+27.0) 
4.85 (+54.2) 
5.22 (+63.5) 
5.54 (+76.1) 
5.48 (+74.2) 
5.50 (+74.9) 
4.71 (+49.7) 

(c) 

VI 



252 



(EDEMA AND NEPHRITIS 



reached a certain concentration, or has acted upon the tissue col- 
loids for a certain length of time, or both, and that the loss of 
water is associated with a change in the colloids (denaturation?) 
whereby these are changed from such as have hydrophilic charac- 
teristics into such as have more decided hydrophobic charac- 
teristics. 

Since the formation of acid in tissues deprived of a circu- 
lation is a firmly established fact — a fact which in these ampu- 
tated frogs' legs can be verified through mere application of an 
indicator — we have no difficulty in interpreting these experiments 
by saying that the amputated frogs 7 legs swell in water because 
the hydration capacity of their colloids is increased through the 
production in them of acid. The frogs' legs become edematous 
for the same reason that fibrin swells more in a dilute acid than in pure 
water. 

(c) If instead of being placed in distilled water the amputated 
TABLE LXXX 



Frogs' Legs 



Hours in the 


110 cc. H 2 0. 


10 cc. m/1 


i 

15 cc. m/1 


solution. 




NaCl+100 cc. H2O. 


NaCl+95 cc. H 2 0. 




% 


% 


% 





3.42 (0) 


3.42 (0) 


3.055 (0) 


1.25 


3 . 55 ( + 3.8) 


3 . 48 ( + 1.7) 


3.065 (+ 0.3) 


4.40 


3 . 74 ( + 9.3) 


3.59 (+ 4.9) 


3.09 (+ 1.1) 


21.15 


4.41 (+28.9) 


4.02 (+17.5) 


3.37 (+10.3) 


29.15 


4.71 (+37.7) 


4.19 (+22.5) 


3.52 (+15.4) 


43.00 


5.03 (+47.0) 


4.49 (+31.2) 


3.74 (+22.4) 


77.15 


5.00 (+46.1) 


4.95 (+44.7) 


4.19 (+36.1) 


96.15 


4.32 (+26.3) 


4.83 (+41.2) 


3.98 (+30.2) 




(a) 


(a) 


(b) 






I ' 


II 


Hours in the 


20 cc. m/1 


25 cc. m/1 


30 cc. m/1 


solution. 


NaCl+90 cc. H2O. 


NaCl+85 cc. H 2 0. 


NaCl +80 cc. H 2 0. 




% 


% 


% 





2.95 (0) 


2.87 (0) 


2 . 85 (0) 


1.25 


2.93 (- 0.7) 


2.81 (- 2.1) 


2 . 77 ( - 2.8) 


4.40 


2.87(- 2.6) 


2.74 (- 4.5) 


2.68(- 5.9) 


21.15 


2.93 (- 0.7) 


2.69 (- 6.3) 


2.59 (- 9.1) 


29.15 


3.01 (+ 2.0) 


2.73 (- 4.9) 


2.63(- 7.7) 


43.00 


3.18(+ 7.7) 


2.95 (+ 2.8) 


2.91 (+ 2.1) 


77.15 


3.63 (+26.0) 


3.49 (+21.6) 


3.53 (+23.8) 


96.15 


3.36 (+14.2) 


3 . 53 ( +23 . 0) 


3.50 (+22.8) 




(b) 


(c) 


(c) 




III " 


IV 


V 



(EDEMA 



253 



frogs' legs are dropped into any salt solution, they swell less than 
in distilled water. The higher the concentration of the salt, the 
less will the frogs' legs swell. These statements are entirely 
analogous to those made regarding the swelling of protein colloids 




in dilute acid solutions, and are illustrated in Figs. 98, 99, 100, 
and 101. 

In Fig. 98, based on the experimental findings contained in 
Table LXXX, the curves for the swelling of the amputated frogs' 
legs lie progressively lower with every increase in the concentra- 
tion of the sodium chlorid. 



254 



(EDEMA AND NEPHRITIS 



(d) When the effect of equimolar salt solutions on the swelling 
of amputated frogs' legs is compared, it is found that some allow 




a greater swelling than others. This is shown in Figs. 99, 100, 
and 101. 



(EDEMA 



255 



The action of a series of chlorids is shown in Fig. 99. We 
have no difficulty in recognizing the following general grouping 
of the basic radicals in which that least effective in preventing 
the swelling is placed 

first: ' r-r-n " n n — 18 

Lithium 

Sodium 
Ammonium 
Potassium 



Calcium 
Barium 
Magnesium 
Strontium 



Copper (ic) 
Iron (ic) 



The general grouping 
of these basic radicals is 
identical with that given for 
their effect on the swelling 
of fibrin (also gelatin 
gluten, aleuronat, muscle, 
eyes and nervous tissue) 
in the presence of acid. 

Fig. 100 allows the 
comparison of a number 
of sodium salts. 

The various acid radi- 
cals arrange themselves in 
the following order, that 
least effective in prevent- 
ing the swelling being 
placed first: 




Bromid 

Chlorid 

Bicarbonate 

Nitrate 

Acetate 

Sulphate 

Tartrate 

Phosphate 



256 



CEDEMA AND NEPHRITIS 



The order is practically identical with that given for the relative 
effect of different acid radicals on the swelling of protein colloids 
in the presence of acid. 

Fig. 101 shows the curves obtained with a series of potassium 
salts, The acetate and nitrate curves lie somewhat high. Other- 




wise the order is the same as already given for the sodium salts. 
Of much interest is the great inhibition in swelling induced by 
the citrate solution, in which the frog leg loses most heavily. 

The experimental data from which Figs. 99, 100, and 101 are 
constructed are contained in Tables LXXXI, LXXXII, and 
LXXXIIJ 



(EDEMA 



257 



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258 



(EDEMA AND NEPHRITIS 



TABLE LXXXII 

Frogs' Legs 



Hours in the 
solution. 


15 cc. m/1 
sodium acetate 
+95 cc. H 2 0. 


15 cc. m/1 
sodium bromid 
+95 cc. H 2 0. 


15 cc. m/1 
sodium bicarbonate 
+95 cc. H 2 0. 


15 cc. m/1 
sodium chlorid 
+95 cc. H 2 0. 




3.35 
17.30 
27.15 
31.45 
70.35 
100.55 


% 

3.39 (0) 
3.36 (-1.0) 
3.34(-1.6) 
3.36 (-1.0) 
3.43 (+1.0) 
3.55 (+4.2) 
3.66 (+7.8) 


% 

3.42 (0) 
3.47 (+ 1.4) 
3.71 (+ 8.4) 
3.86 (+13.1) 
4.24 (+24.0) 
4.46 (+30.4) 
4.70 (+37.4) 


% 

3.33 (0) 
3 . 33 (0) 
3.45 (+ 3.6) 
3.59 (+ 7.8) 
3.95 (+18/6) 
4.19 (+25.8) 
4.44 (+33.3) 


% 

3.25 (0) 
3.25 (0) 
3.37 (+ 3.7) 
3.53 (+ 8.6) 
3.96 (+21.8) 
4.28 (+31.6) 
3.86 (+18.7) 


Hours in the 
solution. 


15 cc. m/1 
sodium nitrate 
+95 cc. H 2 0. 


15 cc. m/1 
disodium hydro- 
gen phosphate 
+95 cc. H2O. 


15 cc. m'/l 
sodium sulphate 
+95 cc. H 2 0. 


15 cc. m/1 
sodium-potas- 
sium tartrate 
+95 cc. H2O. 




3.35 
17.30 
27.15 
31.45 
70.35 
100.55 


% 

3.49 (0) 
3.47(- 0.5) 
3.56 (+ 2.0) 
3.70(+ 6.0) 
4.19 (+20.0) 
4.58 (+31.0) 
4.33 (+24.0) 


% 

3.48 (0) 
3.35 (-3.7) 
3.18 (-8.6) 
3.17 (-8.8) 
3.25 (-6.6) 
3.48 (0) 
3.69 (+5.9) 


% 

3.95 (0) 
3.84 (-2.7) 
3.71 (-6.0) 
3.67 (-7.0) 
3.74 (-5.3) 
3.88 (-1.7) 
4.10 (+3.7) 


% 

3 . 74 (0) 
3.64 (-2.6) 
3.51 (-6.1) 
3.49 (-6.6) 
3.53 (-5.6) 
3.58 (-4.2) 
3.73 (-0.2) 



(e) The addition of various non-electrolytes does not at the same 
" osmotic " concentration affect the amount of water that will be ab- 
sorbed by amputated frogs' legs as greatly as does the addition of 
electrolytes. I have tried ethyl and methyl alcohols, urea, 
glycerin, dextrose and cane-sugar. Urea increases somewhat the 
tendency to swell. In solutions of the remaining non-electro- 
lytes the absorption curves are almost identical with those given 
in Fig. 97 for absorption from distilled water. 

These experiments indicate satisfactorily that the absorp- 
tion of water by a whole member such as a leg is dependent upon 
the state of the colloids contained in it. Its normal hydration 
capacity is raised when acids develop in it, and as all salts coun- 
teract the effect of an acid in favoring the swelling of a (hydro- 
philic) protein colloid, not only according to their concentra- 
tion, but also according to their chemical character, so also do 
they counteract the cedema of an amputated frog's leg. Non- 
electrolytes which are comparatively ineffective in reducing the 
swelling of protein colloids are also incapable of reducing the 
absorption of water by an amputated frog's leg. 



(EDEMA 



259 



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260 



(EDEMA AND NEPHRITIS 



It has been objected to these experiments that they deal 
with " dead " animal tissues and that in consequence the facts 
learned upon them may not be applied to the " living " cedemas 
which we encounter clinically. Absurd as is such reasoning it is 
easily met. Various salts reduce the oedema produced in living 
frogs by any means whatsoever just as readily as they reduce the 
oedema observed in amputated frogs' legs. The injection of a poison 
like uranyl nitrate produces in a short time a marked cedema in 
frogs. This can be greatly reduced in severity if the animals, 
instead of being kept in distilled water, are kept in various salt 
solutions. The following experiments serve to illustrate this fact: 

Experiment 10. — Twelve frogs that have been kept in jars of 
tap water for several days have the urine squeezed from their blad- 
ders, are weighed, and divided into two sets of six each in such a way 
that the weight of any one frog in the first series is about that of a 
corresponding one in the second series. They are then all injected 
with 0.2 gram uranyl nitrate into the dorsal lymph sac and placed 
in separate finger bowls each containing 100 cc. distilled water in 
the first series and 100 cc. Ringer solution in the second. The fluid 
in the bowls is changed once in twenty-four hours. The changes in the 
weights of the frogs are indicated in the tables on page 261. 

Experiment 11. — Six frogs are weighed, each injected with 0.05 
gram uranyl nitrate into the dorsal lymph sac, and divided into two 
sets of three each. Those of the first are kept in finger bowls 
each containing 100 cc. water; those of the second in bowls containing 
100 cc. 1/6 molar sodium chlorid solution. The changes in weight are 
as follows : 



Series in Water 



Hours. 


1 


2 


3 


Average. 





30 % 


27 % 


24 % 





18 


33 (+10.0) 


? 


28 (+16.6) 


+13 3 


26 


36 (+20.0) 


30.5(+12.9) 


29 (+20.8) 


+17.9 


42 


37 (+23.3) 


35 (+29.6) 


29.5 (+22.9) 


+25.3 


68 


38 (+26.6) 


41 (+51.8) 


? 


+39.2 


92 


39 (+30.0) 


Dead 


30 (+25.0) 


+27.5 


Series in m/6 NaCl (0.975%). 


Hours. 


I 


II 


III 


Average. 





34 % 


29 % 


26 % 





18 


32(- 5.8) 


29 (+ 0) 


26 (+ 0) 


- 1.9 


26 


33 (- 2.9) 


30 (+ 3.4) 


27 (+ 3.8) 


+ 1.4 


42 


33 (- 2.9) 


31 (+ 6.8) 


28 (+7.7) 


+ 3.9 


68 


38 (+11.7) 


33 (+13.8) 


30 (+15.3) 


+13.6 


92 


39 ( + 14.7) 


35 (+20.7) 


Dead 


+17.7 



(EDEMA 



261 



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262 



(EDEMA AND NEPHRITIS 



Incidentally these experiments show that, contrary to much 
clinical teaching, administration of sodium chlorid does not increase 
an existing oedema. We shall have occasion to return to this 
question later, but we already see that sodium chlorid is no 
exception to the general rule that the presence of salts leads to 
dehydration of protein colloids. 

The effect of sodium chlorid in reducing an oedema is evident 
to mere inspection. In Fig. 102 a and b, is shown the untreated 
Frog 3 of Experiment 11, photographed at the time of injec- 
tion and forty-two hours later. Fig. 103, a and b, shows Frog III 
treated with sodium chlorid and similarly photographed. 

4. On (Edema Due to Other than Acid Causes 

Unfavorable criticism of the colloid-chemical theory of water 
absorption as applied to the problem of cedema has spent its force 
but little upon our fundamental contention that the hydro- 
philic colloids and their state of increased hydration character- 
izes this pathological entity, but rather upon the entirely sub- 
sidiary one of the mechanism by which the normal hydration 
capacity of any hydrophilic tissue colloid is raised to the degree 
accepted as characteristic of " oedema." In discussing this 
lesser phase I have laid chief stress on the importance of an 
abnormal production and accumulation of acid in the affected 
part. My critics have for various reasons, adequate in their 
judgment, denied the effectiveness of this factor, but, with the 
exception of W. J. Gies, none has contributed any new sugges- 
tions as to what might be responsible for the increased hydra- 
tion if a production or accumulation of acid were not. 

Let me first reemphasize that I have never held an acid 
production and accumulation to constitute, of necessity, the 
only factor responsible for the increased hydration which charac- 
terizes cedema. I pointed out even in my first papers 1 that a 
conversion of colloid material of one type into another more 
highly hydrated type might lead to cedema, and emphasized the 
importance of Wolfgang Ostwald's findings in this connec- 
tion, according to which Beta-gelatin swells more than the ordi- 
nary kind. Since Beta-gelatin is a partly hvdrolyzed one, and 
since this change has much in common with the first changes 

1 See the bibliography at the end of this volume. 



(EDEMA 



263 




(EDEMA 



265 



of protein digestion under the influence of proteolytic ferments, 
it was but natural that the possible importance of these in the 
production of cedema should come to mind. William J. Gies 1 
has since insisted upon this point anew. The ultimate acceptance 
or rejection of the importance of this element in the problem 
must depend upon experiment. Thus far it has not been demon- 
strated that the ferments play any great role in increasing the 
water content of proteins, and there are absolutely no sugges- 
tions at hand as to how in cedema the chemistry of normal cellu- 
lar activity becomes so upset as to allow the ferments then to 
do things which they do not do normally. The quantitative 
experiments of Grover Tracy, Frank R. Elder and William 
J . Gies 2 — and such only can tell us of the relative importance 
of different agencies in hydrating colloids — show proteolytic 
ferments to increase water absorption under optimal conditions 
only some three to six parts, when acid alone has already made^ 
the proteins take up from seventy to eighty times their original 
weight. But what is of greater significance for the biological 
aspects of the problem are the more recent experiments of Edgar 
G. Miller, Jr., and Gies, 3 which confirm an older observa- 
tion of my own 4 that tissues exposed to autolytic changes 
swell no more than fresh tissues subjected to the same external 
conditions. 

Bej^ond this my critics have been entirely barren of sug- 
gestions regarding other agencies which in biological material 
might be capable of increasing its hydration capacity. In col- 
loid chemistry we know, of course, a number which increase 
the hydration of protein colloids, but it is quite another matter 
whether these ever appear in living material in sufficient 
amounts or are there sufficiently active to give rise to such 
cedemas as are encountered clinically. The only way in which 
such questions can be settled is by direct animal experiments. 
Such are simple enough in themselves and it would seem an easy 
matter to determine whether or not certain substances which 
increase the hydration of proteins in vitro do this also in living 

1 William J. Gies, Biochem. Bull. 1, 312 (1911). 

2 Grover Tracy and William J. Gies: Biochem. Bull., 1, 467 (1912); 
Frank R. Elder and Gies: ibid., 1, 540 (1912). 

3 Edgar G. Miller, Jr., and William J. Gies: Biochem. Bull., 1, 475 
(1912). 

4 See page 251; or page 111 of the first edition of (Edema. 



266 



(EDEMA AND NEPHRITIS 



animals. But it is not always easily proved that in the latter 
case the given substance did this directly, and not indirectly 
as by interfering with the normal oxidation chemistry of the body 
cells, or by interfering with normal cardiac or respiratory activity. 
Tentatively, however, the following facts may prove of interest 
in connection with the general problem of oedema production 
in animals by means 1 other than the introduction, production or 
accumulation of acids in them. 

It does not surprise us that frogs develop an cedema if kept 
in solutions containing alkali in toxic amounts. Alkali effectively 
hydrates protein in vitro and it does this in vivo. To shut out 
the factor of acid production (through muscular work) conse- 
quent upon the movements of the frog in the alkaline solution it is 
well to destroy the brain. 

The accumulation of urea (and other nitrogenous products) 
in the blood and tissues of patients likely to show cedema (as in 
the nephritides) and its proved capacity of increasing the hydra- 
tion of protein, suggested that an accumulation of urea might 
be one of the factors in determining the development of cedema 
in certain clinical cases. Experiments on frogs as thus far per- 
formed do not, however, lend any support to such a conclusion. 
If urea is of importance in leading to a development of cedema 
its role from a quantitative standpoint is rather small. Its bio- 
logical importance from a qualitative standpoint may, however, 
be great because of the peculiar type of hydration which it pro- 
duces and because it makes proteins readily able to go into " solu- 
tion." 

Both pyridin and some of the amins (ethyl and diethyl amin) 
lead to marked oedema in frogs. The amins are peculiarly 
powerful in their action, exceeding both in rate of development 
and in the intensity of the cedema produced all alkalies of the 
same concentration. This observation seems to me of funda- 
mental importance in connection with the cedemas accompany- 
ing some of the infections, for the amin character of many of 
the toxins is a proved matter. 

The qualitative and quantitative characteristics from an 
cedema-producing point of view of the materials produced in any 

1 See Martin H. Fischer and Anne Stkes: Science, 38, 486 (1913); 
Jour. Med. Soc, New Jersey, 11, 116 (1914); Kolloid-Zeitschr., 14, 215 
(1914); ibid., 16, 129 (1915). 



(EDEMA 



267 



ordinary infection are well illustrated by such analyses as those of 
0. Emmerling. 1 From a culture medium of 860 grams of egg 
white * inoculated with staphylococcus pyogenes aureus Emmer- 
ling isolated an uncalculated amount of formic acid, 2.5 grams 
acetic acid, 0.6 gram propionic acid, 10.8 grams butyric acid, 0.5 
gram other fatty, acids, 2.0 grams oxalic acid, 0.3 gram succinic 
acid and 3.5 grams trimethylamin. From 600 grams moist wheat 
gluten inoculated with proteus vulgaris he isolated large amounts 
of formic, acetic and butyric acids (18 grams of the latter) as well 
as some of the higher fatty acids. He obtained also 0.65 gram 
phenol, more than 5.0 grams of ammonia 2 and appreciable quan- 
tities of trimethylamin. Aside from the fact that there is no 
unanimity regarding what constitutes a toxin and the further 
fact that the work of such men as Brieger shows that the staphy- 
lococci produce no substances which satisfy the qualifications of 
the toxins, the question may well be asked, need we have recourse 
to such hypothetical compounds to explain the tissue changes 
either locally or constitutionally produced by an infecting organ- 
ism? The analyses of Emmerling show that sufficient quantities 
of easily isolated and simple chemical compounds are produced 
in the course of the ordinary infections to account readily for even 
the most destructive changes observed either clinically or post- 
mortem. The significance of such values for the understanding 
of the etiology, pathology and treatment of the changes incident 
to the infections needs no comment. 

A series of important observations made by Allan Eustis 3 
fit in here. Eustis has for several years insisted on clinical 
grounds, as have others, upon the importance of protein deriv- 
atives in the production of certain cedemas such as bronchial 
asthma and urticaria. His clinical experience has, however, been 

1 0. Emmerling: Ber. d. deut. chem. Gesellsch., 29, 2721 (1896). 

2 Allan Eustis has called my attention to the fact (Personal commu- 
nication (1920) ) that much of the so-called ammonia fraction obtained in 
analyses of the blood, urine and other body fluids, is probably not at all 
attributable to the existence of ammonia as such in these fluids, but repre- 
sents ammonia produced in the process of analysis from decomposition of 
various amins. Considering the tremendous hydrating properties (oedema- 
producing properties) of the amins, it is small wonder that swelling is the 
commonest accompaniment of all the ordinary infections in which a decom- 
position of protein material occurs under the influence of pathogenic organisms 
in the living animal body. 

3 Allan Eustis: Am. Jour. Med. Sci., 143, 862 (1912); New Orleans 
Med. and Surg. Jour., 66, April (1914). 



268 



(EDEMA AND NEPHRITIS 



supported by experiment, in that he has shown that betaimid- 
azolylethylamin (a putrefaction product of the histidin nor- 
mally produced in digestion) when applied to the slightly broken 
skin is followed by an intense urticarial-like eruption. 

IV 

ON THE PASSIVE CONGESTION (EDEMAS OF THE KIDNEY 
AND THE LIVER 

It is our next problem to discuss some special aspects of cedema, 
in so far as such affects certain organs or constitutes the prominent 
feature of special pathological or clinical states. Nephritis, for 
example, is in good part an cedema of the kidney, glaucoma an 
cedema of the eye, uremia an cedema of the brain; on the other- 
hand, a deficient urinary output, an increased intraocular tension 
or a coma are but the clinical parallels if not the direct expressions 
of these cedemas. Because of their great clinical interest, glau- 
coma, nephritis and uremia receive detailed discussion later. 
Here we want to touch upon certain other aspects of cedema not 
discussed there which in addition to bringing further evidence 
for the colloid-chemical concept of cedema serve also to illustrate 
how I think we must interpret, and more correctly, certain well- 
known and long-recognized pathological and clinical facts. 

How, on the basis of the foregoing discussion, are we to under- 
stand the so-called passive congestion ozdemas of the kidneys and 
the liver? In consequence of interference with the outflow of 
blood from these organs, be this due to a merely local disturbance, 
such as pressure upon the efferent vein, or to a more general one, 
such as heart disease, they become filled with blood and increase 
in size. The increase in size is independent of the presence of an 
excessive amount of blood in the organ; it is due, in other words, 
to an increase in the size of the individual cells and tissues them- 
selves — an cedema. For this oedema of the parenchimatous 
organs the same factors of increased blood pressure, increased 
permeability of blood vessel walls, etc., that are so familiar to 
us from our previous considerations, have again been held respon- 
sible. In fact, the deductions made from consideration of the 
well-defined passive congestion cedemas of various organs as 
observed clinically or produced experimentally may be said to 



(EDEMA 269 

have colored our whole conception of the essential nature of 
all classes of oedema. 

There exists no dearth of isolated experimental and clinical 
observations on the passive congestion cedemas of the liver and 
the kidney, but the attempts that have been made to correlate 
them can hardly be said to have proved successful. Adherents of 
the pressure theory of oedema, for example, cannot meet the 
fact that an increase in blood pressure is all too often absent in 
patients with marked " congestion " of the kidneys or liver; 
that swollen, passively congested organs decrease in size after the 
use of drugs whose chief action makes for an increase in blood 
pressure; and that enormous experimental increases in blood 
pressure in animals do not lead to cedemas of these organs. On 
the other hand, believers in the increased permeability of blood 
vessel walls have never proved their point physico-chemically ; 
nor have those who have recently resurrected the role of hydremia 
forty years after Cohnheim buried it experimentally. 

On the colloid-chemical basis we interpret the phenomena 
that characterize the passive congestion cedemas of kidneys 
or liver as follows: The cause of the oedema is again to be sought 
in the tissues. The circulatory disturbances leading to an oedema 
of these organs all have this in common: they bring about a state 
of oxygen want in the tissues in consequence of which acids are 
produced in them. These increase the capacity of the tissue colloids 
for holding water, whereby they are enabled to absorb an increased 
amount from any available source. This idea is supported by the 
following: 

§ i • 

It is a well-known fact that when the efferent (renal) vein 
of the kidney is tied in animals, the organ becomes filled with 
blood, while the kidney tissues proper swell and become pro- 
gressively firmer in consistence. This is the typical picture of 
a passive congestion sufficiently severe to permit of the develop- 
ment of an oedema in the congested area. We need not repeat 
that what happens in this experiment is usually interpreted as 
an oedema due to an increased blood pressure, alterations in 
vascular permeability, etc. All these explanations fall as soon 
as it is stated that ligation of the renal artery leads to the same 
series of changes in the kidney as ligation of the renal vein (with 



270 



(EDEMA AND NEPHRITIS 



the exception of the overfilling of the blood vessels). (See 
Fig. 104.) 

An abstract of a few experiments carried out with Gertrude 
Moore 1 on rabbits may serve to illustrate this point. In a series 
of nine Belgian hares we ligated the left renal vein in three and 
the left renal artery in the remaining six. The operations were 
made under morphin anesthesia, and in no case consumed more 




A B 

Figure 104. — A, normal right kidney; B, oedematous left kidney of the 
same rabbit twentv-three hours after ligation of the renal arterv. Experi- 
ment " IV" of May 13, 1909. 



than five minutes. None of the operations was complicated 
by infection. At various periods after the operations the 
animals were killed and the two kidneys of each animal weighed. 
As clearly apparent from the following tables, the increase in 
the weight of the kidney after ligation of the artery is quite as 
great as after ligation of the vein. The extra amount of clotted 
blood found in the kidney when the veins are ligated easily 
accounts for the somewhat higher values found in Table LXXXIV 
over those found in Table LXXXV. 

1 Martin H. Fischer and Gertrude Moore: Kolloid-Zeitschr., 5, 286 
(1909). 



OEDEMA 



271 



TABLE LXXXIV 
Ligation of Left Renal Vein 



Rabbit. 


Weight of 
rabbit. 


Hours after 
ligation. 


Weight of kidneys. 


Gain in weight 
in % of 
normal. 


Normal. 


Ligated. 


May 13, '09, "VI". . . 

May 1, '09, "C" 

May 13, '09, "V" 


930 
1500 
811 


19.20 
22.10 
42.40 


4.20 
7.50 
3.80 


7.00 
12.70 
13.95 i 


66.6% 
69.3% 
267.1% i 



1 This unusually high figure was due to the fact that an enormous extravasation of 
blood into the capsule with oedematous swelling occurred in this case. 



TABLE LXXXV 



Ligation of Left Renal Artery 









Weight of kidneys. 


Gain in weight 




Weight of 


Hours after 






in % of 


Rabbit. 


rabbit. 


ligation. 






normal. 








Normal. 


Ligated. 




May 13, '09 "I" 


970 


4.25 


5.60 


' 6.50 


16.1% 


May 13, '09, "III". . . 


1127 


19.00 


5.07 


7.95 


56.8% 


May 13, '09, "IV". . . 


1115 


23.00 


4.75 


7.42 


56.4% 


May 1, '09, "A" 


1500 


23.00 


7.43 


11.70 


57.3% 


May 13, '09, "II" 


734 


42.15 


3.63 


6.65 1 


83.2% i 


May 1, '09, "B" 


1560 


48.00 


7.40 


10.65 


43.9% 



1 This high value was due in part to an extravasation of blood into the capsule with 
cedematous swelling. Note that the escape of blood occurred after ligation of the artery 
(diapedesis without blood pressure!). 



A decrease in blood pressure is, therefore, quite as effective 
in bringing about an oedema of the kidney as an increase. While 
such. a result is unexplainable on the basis of the widely accepted 
pressure theory of oedema it is not surprising to us. In fact, such 
an experimental result was anticipated. Ligation of the vessel 
which carries the arterial blood to an organ must of necessity 
lead to a state of oxygen want in the tissues quite as readily 
as ligation of the vessel which carries the venous blood away. 

We turn now to the liver, where, owing to the anatomical 
peculiarities of its vascular supply, valuable conditions are offered 
for experiments with which to test further this colloid concep- 
tion of oedema. 

The kidney is supplied with blood through the renal artery, 
which it will be recalled is very large as compared with the size 
of the organ. The physiological purpose of this anatomical 
arrangement is not far to seek. Through this artery there must 



272 



(EDEMA AND NEPHRITIS 



pass to the kidney not only enough blood to supply the kidney 
tissues with oxygen, but all that blood from which the kidney 
separates the urine. In the case of the liver the blood supply 
is quite different. Through the venous portal blood the char- 
acteristic functions of the liver are subserved; through the 
arterial blood furnished by the hepatic artery the parenchyma is 
supplied with its necessary oxygen. Both these streams unite 
to leave the liver through the hepatic vein. 

When now a liver becomes decidedly cedematous from 
passive congestion, say in consequence of a heart lesion or pressure 
upon the hepatic vein, how is this result to be interpreted? 

After our remarks on the essential role played by oxygen want, 
and not mere blood pressure changes in the production of oedema 
in the kidney, the well-known fact that ligation of the portal 
vein is not followed by an oedema of the liver does not surprise 
us — the portal vein carries only venous blood to the liver, and 
so changes in its parenchyma due to a production of acids are 
not to be expected. Quite a different picture is obtained when 
the hepatic artery is ligated. In spite of the fall in blood pressure 
brought about by this means the liver rapidly develops an intense 
oedema. This result is quite expected on the basis of our theory, 
and indicates clearly that the real reason why a passive conges- 
tion leads to an oedema of the liver is because it interferes with 
the necessary flow of arterial blood through the organ via the hepatic 
artery. 

The following four experiments show how quickly ligation 
of the hepatic artery in rabbits leads to oedema of the liver, 
and how severe this is. The oedema follows ligation the more 
rapidly and is the more intense the more perfect the ligation of 
the various branches that constitute the hepatic artery in this 
animal. The operations were again made under morphin 
anesthesia, in ten to fifteen minutes and without infection. The 
increase in the size of the liver, while readily apparent to the 
eye, can be expressed numerically only by indirect calculation of 
the weight of the liver in percentage of the body weight of the 
operated animal. In a series of six normal rabbits we found the 
liver to constitute 2.9 per cent, 3.2 per cent, 3.5 per cent, 3.7 per 
cent, 3.7 per cent, and 3.7 per cent (an average of 3.45 per cent) 
of the total body weight. Table LXXXVI shows how much the 
liver is increased in size when the hepatic artery is ligated. 



(EDEMA 



277 



this conception pulmonary cedema is placed in the general 
group of Julius Cohnheim's 1 congestion cedemas. 

Welch's ideas have not gone unchallenged. Through the 
observations of various authors, particularly H. Sahli 2 and M. 
Lowit 3 it has been proved beyond doubt that the severest grades 
of pulmonary cedema may exist clinically and be produced 
experimentally without any evidence of an increased pressure 
in the pulmonary circuit. Welch's theory has in consequence 
been variously modified or cast aside entirely. We hear again 
of " increased permeability of blood vessel walls," of " hydremia," 
of " secretory " disturbances, of still more vague " irritations," 
and, when all these fail, of changes in the peculiar " life " of the 
cells themselves. The views held by the various authors are so 
divergent and at times so flatly contradictory that a detailed 
discussion of them is purposeless. The vagueness of these 
theories stands in sharp contrast to the really excellent experi- 
mental and clinical observations that are available. A unifying 
interpretation of these is still lacking. Toward such the follow- 
ing is offered : 

The problem of pulmonary oedema is identical with the problem 
of oedema in such an organ as the liver. The reason for this 
is at once apparent when we call to mirid that the vascular 
arrangement in the lungs is similar to that which we previously 
discussed for the liver. Just as the liver, so is the lung supplied 
with two blood streams — with a venous stream through the 
pulmonary artery, which only passes through the lung for 
purposes of oxygenation, and an arterial stream through branches 
from the thoracic aorta, the bronchial arteries, which supplies 
the parenchyma of the lung with oxygen. The blood brought 
by these nutrient arteries leaves the lung in part through the 
bronchial veins, in part admixed with the blood of the lesser 
circulation through the pulmonary veins. The facts at hand on 
the experimental production of pulmonary oedema are easily 
interpreted by saying that an oedema results whenever the oxygen 
supply to the parenchyma of the lung is sufficiently interfered 
with. 

1 Julius Cohnheim: Allgemeine Pathologie, 2d Ed., 1, 501, Berlin 
(1882). 

2 H. Sahli: Arch. f. exp. Path. u. Pharm., 19, 431 (1885). 

3 M. Lowit; Ziegler's Beitrage, 14, 401 (1893). 



278 



(EDEMA AND NEPHRITIS 



If the pulmonary arten r passing to one lung is ligated, no 
oedema results. If, in addition, most of the branches passing to 
the opposite lung are similarly treated, we still get no oedema. 
Enough circulation needs only to be maintained through the lung 
to keep the animal alive. This result is, to our mind, entirely 
to be expected, for such ligations do not interfere with the oxygen 
supply to the parenchyma of the lung. Ligation of the pul- 
monary veins may lead to oedema of the lungs, but only if suf- 
ficiently extensive to shut off most of the blood as it returns 
from the lung. In other words, it is not an easy matter to dam 
back the blood in the bronchial arteries (which discharge in part 
into the bronchial veins, in part into the pulmonary veins) by 
ligating only the pulmonary veins. These experiments show 
that interferences with the pulmonary circulation itself are, 
on the whole, scarcely able to lead to an oedema of the lung. 

The most effective way to bring about a pulmonary oedema 
is to disturb the systemic circulation. Compression of the left 
ventricle leads to pulmonary oedema, as does ligation of the 
aorta either at its root or not lower than the point of origin of 
the left subclavian artery. Ligation of the thoracic aorta 
low down, or of the abdominal aorta, does not lead to pul- 
monary oedema. These undisputed experimental, facts are 
hard to understand on the basis of any pressure theory. While 
a rise of blood pressure in the pulmonary circuit may well be 
present in all these experiments, why should it be more effective 
when induced through ligation of the aorta than through direct 
ligation of the pulmonary vein? And why should ligation of 
the aorta to just below the left subclavian artery lead to a pul- 
monary oedema, and ligation just a little lower down be inef- 
fective? Only a few small arteries are given off by the thoracic 
portion of the descending aorta. We experience no difficulty 
in interpreting all these findings when we recall that the bronchial 
arteries leave the aorta just below the left subclavian. Compression 
of the left ventricle and ligation of the aorta to just below the sub- 
clavian all spell a lack of oxygen for the lung parenchyma, and 
hence an oedema. A ligation just below the bronchial arteries is 
without effect in this regard. 

These experiments show that a pulmonary oedema develops 
under the same conditions as an oedema anywhere else — whenever 
the lung parenchyma is placed in a state of lack of oxygen. This 



(EDEMA 



279 



state of oxygen want we always discovered to be important 
in other organs because it led to an abnormal accumulation or 
production of acids in the tissues. That such conditions prevail 
when the lungs become cedematous is borne out, not only by the 
fact that a pulmonary oedema is never induced in any animal 
by the various ligations described above without gross evidences 
of improper aeration of the blood, but by the following facts 
regarding chemically induced oedemas, and the cedemas of 
excised lungs. 

Pokrowsky, Friedlander, and Herter 1 found that rabbits 
and dogs which had breathed for some time an atmosphere 
rich in carbon dioxid showed grades of pulmonary oedema at 
autopsy which varied from such as were scarcely recognizable 
to such sufficiently intense to kill the animals. (Edemas have 
also been noted after inhalation of the fumes of various other 
acids. Other chemical methods of inducing a pulmonary oedema 
lead to a state of lack of oxygen and acid production in the tissues 
in a more indirect way. Under this heading come hydrocyanic 
acid, various ethers and anesthetics, carbon monoxid, adrenalin, 
and iodin — all of them substances which we know interfere 
markedly with the normal oxidations of living cells. 

The clinical evidence that pulmonary oedema is more often 
an accompaniment of the oedema of nephritis than of the oedema 
of heart disease is also easily understood on the basis of this 
chemical origin of pulmonary oedema. In nephritis we have 
the toxic bodies which are responsible for the oedema of the kidney 
more or less uniformly distributed throughout all the tissues of 
the body. The parenchyma of the lungs is therefore as likely to 
be affected by these toxic bodies as the parenchyma of any other 
organ. 2 In heart disease, on the other hand, the severity of the 
oedema of any organ is distinctly dependent upon the quality of 
the circulation going through this organ which in turn determines 
the amount of oxygen furnished the organ and the readiness with 
which the carbonic acid formed in it is carried away. Generally 
speaking, the greater the distance of an organ from the left ven- 

1 Cited from Cohnheim, Allgemeine Pathologie, 2d Ed., 1, 502, and 2, 
273, Berlin (1882). 

2 The pulmonary oedemas seen in patients with blood vessel disease are 
not at once to be attributed to a " nephritis" which they may show. They 
are more commonly the direct consequence of vascular disease involving the 
bronchial arteries. 



280 



(EDEMA AND NEPHRITIS 



tricle, the poorer must be its oxygen supply, and in consequence 
the greater its opportunity to develop an oedema. In heart 
disease the lung is, therefore, of all the organs, in the best position 
to be supplied even to the last, not only with the best oxygenated 
blood available, but with that lowest in carbonic acid. This 
explains why, in spite of much embarrassment in the pulmonary 
circulation, an cedema of the lung need not develop. It does not 
until the lung parenchyma itself suffers from lack of oxygen, a state 
not reached until an inadequate amount of blood, or an inade- 
quately aerated one is supplied through the bronchial arteries. 
Hence the so common terminal pulmonary oedema.- Cohnheim 
has well said, " man does not die because he develops a pul- 
monary oedema, he develops a pulmonary cedema because 
he is dying." The gradually developing lack of oxygen and the 
accumulation of carbonic acid in the lungs in consequence of a 
gradually failing circulation and respiration account for it with- 
out difficulty. 

This conception of pulmonary cedema can be tested in yet 
another way. If the lung becomes ©edematous from any con- 
dition which interferes with a normal oxygen supply to the 
parenchyma, then it ought to be particularly easy to produce 
an oedema in a lung when removed from the body. The most 
intense ozdemas which simulate in every way those observed at the 
autopsy table may be produced in lungs removed from the body, 
and in the entire absence of any such blood pressures as are con- 
sidered active in the current theories of pulmonary oedema. 

The entire uninjured lungs of sheep freshly obtained from a 
nearby slaughter house, and with the heart intact, served for 
material in these experiments. As injection fluids, I used water, 
various salt solutions, dilute acids, and these mixed with salts. 
As the experiments are incomplete I describe only the effects of 
injecting water or m/6 (0.975%) sodium chlorid solution into the 
pulmonary arteries. With use of either of these fluids an intense 
pulmonary oedema results. The experiments are carried out in 
the following way: A cannula is first tied into the pulmonary 
artery; a ligature is next thrown about the heart below the 
cannula, and the heart cut off below this ligature. After adherent 
tags of tissue are removed, the lung is weighed and hung up by a 
ligature drawn through the trachea. If, now, a sodium chlorid 
solution or distilled water is simply allowed to trickle into a funnel 



(EDEMA 



281 



connected with the glass cannula inserted into the pulmonary 
artery, the lung takes up enormous amounts of the fluid in a very 
short time. A lung weighing 500 grams will take up two to three 
liters of either of these fluids in an hour or two. What becomes 
of them is interesting. The lung tissue itself is first affected. 
It swells up enormously (more than doubling in weight after 
infusion for an hour or two), and in the earlier periods of the 
experiment, if the influx of fluid into the pulmonary artery is 
stopped, the lung may be turned upside down and not a drop 
of fluid flow out of either the blood vessels or the trachea. If 
the injection of fluid is continued the pleural surface after a 
time becomes moist, and soon a drop of fluid falls from the lower 
edge of the lung. This is soon followed by another and another 
until a steady drip is established which may amount to several 
hundred cubic centimeters of " pleural exudate " in the course 
of an hour. At the same time the lung can no longer be turned 
upside down without obtaining a bloody, frothy fluid from the 
trachea. This fluid gradually rises in the trachea, and if not 
removed, overflows. The overflow continues as long as the 
infusion of water or salt solution into the pulmonary artery 
is kept up (several hours) . Let it be noted that all this time not 
a drop of fluid comes ou,t of the veins, even though these have 
not been ligated. If the infusion is properly regulated the tissues 
take up all the fluid that passes into the artery, absorb much of it 
themselves, and then alloiv it to pass over into the alveoli and bronchi 
and through the pleura. Even after the infusion of liquid has 
been kept up for several hours, only a few cubic centimeters can 
be recovered from the blood vessels. 

From the experiments that have been carried out thus far it 
may be said that the longer the lungs have been out of the animal, 
the more quickly do these signs of a pulmonary oedema develop. 
Of the various injection fluids used, water leads to the greatest 
oedema of the parenchyma of the lung itself. When any salt solu- 
tion is used this is not so great, but the evidence of fluid in the 
bronchi is obtained earlier, and this " secretion " is more intense. 
Sodium citrate and sodium sulphate are more powerful in this 
regard than sodium chlorid. In other words, the salts which 
dehydrate various protein colloids most are also most powerful 
in dehydrating the pulmonary tissues, and thus of permitting 
the greatest accumulations of fluid in the alveoli. 



282 



(EDEMA AND NEPHRITIS 



We have thus far spoken of pulmonary oedema as a patholog- 
ical entity in the sense in which this term is ordinarily used in 
pathology. But for purposes of discussion and for the ultimate 
solution of the problem I believe that we will have to distinguish 
between the mere presence of an increased amount of fluid in the 
tissues of the lung proper, and the presence of fluid in the alveoli. 
While in the ordinary pulmonary oedema evidence of both is found, 
greatest weight is usually laid on the occurrence of fluid in the 
alveoli and bronchi. When this is present it undoubtedly repre- 
sents the extreme of what we are pleased to call a pulmonary 
oedema. But very severe oedemas of the lung may exist without 
any fluid in the alveoli (as 'in the earlier periods of the oedemas 
produced in excised lungs) . The presence of an excessive amount 
of fluid in the lung tissues proper and the presence of abnormal 
amounts of fluid in the alveoli are rather to be regarded as asso- 
ciated, though not' identical processes. We have no difficulty in 
interpreting all the phenomena of* the oedema of the lung tissue itself 
on the basis of our colloid theory of water absorption. The tissues 
of the lung in pulmonary oedema come to hold an increased 
amount of water because acids are produced in them. Whether 
the possibilities for such an abnormal accumulation of acid are 
offered the lung by ligating various blood vessels in the body or 
by taking it out of the body is immaterial. That water* absorp- 
tion really represents but an excessive hydration of certain 
protein colloids is again proved by the fact that all salt solutions 
inhibit the development of the oedema of the lung tissues proper, 
not only according to the concentration of the salt employed, 
but according to the character of the salt. The citrate and 
sulphate of sodium, for example, inhibit the absorption of water 
by the lung tissues themselves more than the chlorid. Yet 
just the reverse holds regarding the giving off of fluid into the 
bronchi. The explanation of the mechanism by which this 
water is given off is discussed, in part in the next paragraphs 
which consider syneresis in colloids, in part in later chapters 
dealing with secretion. Why the different salts behave as they 
do we shall learn there. 



(EDEMA 



283 



VI 

SYNERESIS AND THE ACCUMULATION OF FLUID IN THE 
BODY CAVITIES IN (EDEMA 

As familiarly known, it is characteristic of the ceclemas 
occurring in the higher animals, for fluid to accumulate in the 
body cavities. In the cedemas of heart disease, for example, 
we observe not only excessive quantities of fluid in the tissues 
themselves, but the pleural, pericardial and peritoneal cavities 
come to contain an abnormally great amount. This fluid is 
not water, but a colloid solution in which the proteins appear 
in lower concentration than in the normal body fluids (blood 
and lymph). Similar serous accumulations occur within the 
tissues themselves. It is generally said that a " transudation " 
of fluid occurs into the tissue spaces, such a space being regarded 
by many as a kind of miniature serous cavity. In truth no 
such cavities of course, exist; they are made by the serous fluid 
as this separates from the more solid (cedematous) tissues. How 
are these accumulations of fluid brought about? 

The explanation has been given by Wolfgang Ostwald 1 
in directing attention to the syneresis exhibited by colloids. 
As first noted by Thomas Graham, hydrated colloids which were 
previously " dry " separate off liquid on standing. The separated 
fluid is not the pure solvent, but a dilute solution of the colloid. 
The classic example of this sort of change is seen in Fig. 105, 
where a silicic acid gel which originally showed no free fluid has, 
on standing, liberated the large amount shown in the photograph 
In doing so the originally more highly swollen gel shrinks, as 
indicated by the space between the edge of the solid colloid 
and the flask. What is important to us biologically is that pro- 
teins show the same type of change. Solid gelatin as well as 
other protein media, as the familiar blood serum of the bacteri- 
ologists, all squeeze off fluid containing protein on standing. 
The bacteriologists call this " water of condensation," but this 
is incorrect, for the fluid is really squeezed out by the protein. 
The more highly hydrated the protein colloid, the more fluid is 
squeezed off. This is shown in Fig. 106. Each of the flasks 
from left to right contains respectively 200 cc. of a 5, 4, 3, and 
1 Wolfgang Ostwald: Personal communication (1913). 



284 



(EDEMA AND NEPHRITIS 



2 per cent solid gelatin. The photograph was taken after the 
flasks had stood for 2\ days in an ice chest. Separation of a 
dilute gelatin solution is evident in the flask on the extreme 

r 




Figure 106. 



right and some has been freed in the flask next to it. No 
separation of liquid occurred in the more concentrated gelatin 
contained in the two flasks on the left. 



(EDEMA 



285 



The accumulation of fluid in the serous cavities and in the 
so-called tissue spaces in edematous states represents the separa- 
tion of a dilute liquid protein colloid from the more solid, heavily 
hydrated ones making up the cedematous tissues themselves. It 
is the analog of syneresis as observable in hydrated colloids. 
As degree of hydration and the time element are of importance 
in determining the amount of fluid that is thus squeezed off 
from laboratory colloids, so also do the high hydration char- 
acteristic of oedema and the time element, as determined by the 
chronicity of the agencies leading to the oedema, play important 
parts in the development of its accompanying " transudations." 

Incidentally, these remarks may suffice to answer the critic- 
ism first raised by W. J. Gies 1 and more recently repeated by 
Felix Marchand, 2 Rudolf Klemensiewicz, 3 C. Ziegler 4 and 
others according to which the colloid-chemical theory of oedema 
is inadequate because there is nothing in the behavior of col- 
loids to explain the mechanism of " transudation." 

VII 

CONCLUDING REMARKS 

It would be a task of purposeless length to review the 
myriad contributions of various authors to the facts and theories 
of. oedema and attempt their reinterpretation in the terms of 
colloid chemistry. To satisfy some of my critics who insist 
on such kindergarten methods it may suffice to indicate the 
road which any such reinterpretation must follow. 

Suppose we choose for comment so simple a fact as that the 
injection of large quantities of " physiological " sodium chlorid 
solution is likely to be followed by some oedema in an animal. 
Does this prove that " increased blood pressure," " plethora " 

*W. J. Gies: Biochem. Bull., 1, 124 and 279 (1911 and 1912); other 
criticisms by Gies as well as my answers to them (ibid., 1, 444 (1912)), are 
also found here. See also F. G. Goodridge and W. J. Gies: Proc. Soc. Exp. 
Biol, and Med., 8, 106 (1911), and my answer in the first edition of my 
"Nephritis" (page 184). 

2 F. Marchand: Verh. d. neut. Naturforsch. u. Arzte (1912). 

3 Rudolf Klemensiewicz : Verh. d. deut. Naturforsch. u. Arzte (1912); 
see also, M. Korner: Transfusion, newly edited by Klemensiewicz, Leipzig 
(1913), where the latter's criticisms are stated more moderately. 

4 C. Ziegler: Verh. d. deut. Naturforsch. u. Artze (1912). 



286 



OEDEMA AND NEPHRITIS 



and " hydremia " are the cause of cedema, as some insist to 
this day, forty years after Cohnheim and Lichtheim and their 
followers showed that no reasonable amount of injected fluid 
ever did this? I think not. 

In a long series of experiments on rabbits, made with an 
entirely different object in view, I found it necessary to inject 
intravenously such amounts of sodium chlorid solution as were 
used by these authors. I found invariably that if the injec- 
tions were only continued long enough the rabbits always devel- 
oped intense general cedemas. The cedema is in other w r ords 
more a function of the time than of the amount of fluid injected. 
How are these cedemas to be interpreted? Simply by noting 
this: Rabbits subjected to such prolonged and great sodium chlorid 
injections suffer from lack of oxygen. In the later hours of the 
experiments this becomes so great that the animals are dis- 
tinctly cyanotic. As soon as we have such a state of lack of 
oxygen we have the conditions at hand that increase the capacity 
of the tissue colloids for holding water, as our previously detailed 
experiments have shown, and so they are in a position to absorb 
water from the circulating liquid in the blood and lymph vessels. 

Just why in such experimentally induced cedemas, the abdom- 
inal organs, for example, should develop the cedema sooner 
than the subcutaneous tissues is a matter that needs separate 
investigation. Predilection for certain regions of the body is 
characteristic also of various clinical forms of cedema (cedema 
of nephritis, cedema of heart disease). The colloids of different 
tissues are different, the demand for oxygen is greater in the 
glandular organs than in the connective tissues, etc. Just how 
the sodium chlorid injections produce the lack of oxygen also 
needs analysis. Simple dilution of the blood, the increased 
work thrown on the heart in pumping this blood, that thrown 
on the various glandular organs in separating the salt solution 
from what is the normal blood, the effect on respiration, etc., 
all have to be considered. 

Another fact is constantly overlooked in experiments on 
cedema made on the higher animals — the necessity of furnishing 
an adequate supply of water to the tissues. This is not easily 
controlled in mammals, and it is for this reason that I chose 
to do most of my experimenting with frogs, which may be 
dropped into water and so be allowed to absorb all they can 



(EDEMA 



287 



take up through the skin. As mammals cannot be relied upon to 
drink voluntarily as much water as we might like to have them 
consume, one is always in the predicament of wondering just 
how much water ought to be injected through the stomach 
tube, and in experiments in which only one part of an animal 
is supposed to become cedematous, an inadequate water supply 
means too often that the affected part, in order to become 
cedematous, must first rob some other tissue with a lesser affinity 
for water before it can satisfy its own needs. After our remarks 
on the role of the colloids in oedema, it is, of course, self-evident 
that the over-consumption of water could not increase an oedema 
after the capacity of the tissue colloids for holding such has 
- once been satisfied. 

There is also no difficulty in understanding why Cohnheim's 
experiments, in which he combined the infusion of sodium 
chlorid solution with moderate injury to a part, always led to 
the development of an oedema in the part more promptly than 
infusion alone. The moderate injury (heat, sunburn, iodin 
application) simply brought about by indirect means, the so 
necessary change in the colloids of the tissues, and the increased 
capacity for holding water once established, the water of the 
sodium chlorid infusion quickly satisfied it. The increased 
swelling of protoplasm after mechanical injury, for example, 
goes down into the very elements of living matter. No more 
brilliant proof of this can be furnished than the observation 
of G. L. Kite 1 who found an immediate localized swelling 
(oedema) to follow the track of his glass needles when pushed 
into the protoplasm of isolated living cells when observed under 
the highest powers of the microscope. 

The interpretation of another experimental observation of 
Cohnheim 2 seems to me to need revision. Cohnheim found 
that an animal which had been bled repeatedly, and injected 
after each bleeding with a sodium chlorid solution, finally 
developed a general oedema, and interpreted this as an oedema 
of cachexia, caused through an increased permeability of the 
blood vessel walls, determined primarily through a hydremia. 
Would it not be simpler to say that through these frequent 

1 G. L. Kite, Personal communication (1913). 

2 J. Cohnheim: Allgemeine Pathologie, 2nd Edition, 1, 498, Berlin, 

(1882.) ' " " ° . 



288 



(EDEMA AND NEPHRITIS 



bleedings the animal became anemic — that is to say, its organs 
got into a state of lack of oxygen — and when a supply of water 
was furnished the tissues, whether through a sodium chlorid 
infusion, or in any other way, they took this up? 

We need not further discuss the inadequacy of all blood or 
lymph pressure theories of oedema. While Cohnheim regarded 
blood pressure as one of the two great factors concerned in the 
production of oedema, he also recognized that severe cedemas occur 
when no change whatsoever in blood pressure is apparent. To 
account for them under such circumstances he had recourse 
to an " increased permeability of the blood vessel walls." If 
in the light of modern physico-chemical conceptions we try 
to say just what is meant by this, we have to define the blood - 
vessel wall as a colloid membrane. From physico-chemical 
observations we know that the permeability of such colloid 
membranes is alterable, so this far Cohnheim is on safe ground. 
But of what consequence would an increased permeability of 
the blood vessels be from a pathological standpoint? To force 
liquids through the blood vessel walls is not to force them into 
the tissues. And the fluid of an cedematous tissue is very 
decidedly in the cells themselves. Cohnheim's hypothesis 
would simply squeeze the oedema fluid as far as the outer walls 
of the capillaries. If we try to aid Cohnheim's conception of 
permeability and make it extend to all protoplasm, then we 
get the cause of oedema right where we have tried to say it is, 
namely, in the tissues themselves; and then our problem is 
simply that of how tissues hold their water. In this the forces 
that have been suggested as active — not only the variable hydra- 
tion capacity of colloids, but even the previously suggested one of 
osmotic pressure, with or without Overton's conception of 
lipoid surface layers — are so infinitely greater than the highest 
grades of blood pressure that pathologists have ever registered 
that the two cannot be compared. 

The more recent experiments of Magnus have added much 
to our knowledge of the experimental side of oedema. His results, 
too, are usually interpreted as lending support to Cohnheim's 
conception of the increased permeability of blood vessel walls 
as a factor in the production of oedema. How well they support 
the belief that the cause of oedema is to be sought in a change 
in the colloid constitution of the tissues is readily evidenced by 



(EDEMA 



289 



the following. Magnus found that animals which are trans- 
fused after death always develop a general anasarca. Living 
animals do not do so as readily, but they do if deeply chloroformed 
or etherized or injected with arsenic. In place of these words 
we could write, placed in a condition of lack of oxygen with an 
adequate supply of water. 

With these remarks, which have been introduced simply to 
illustrate how I think the experimental results of. the score of 
workers who have busied themselves with this problem of oedema 
should be interpreted, we will close our discussion. It is readily 
apparent that through experimental analysis the part played 
by the blood and the lymph circulations has gradually become 
less prominent. From having been looked upon as alone deter- 
mining the amount of water held by the tissues, we have come 
to find that the tissues are largely their own masters in this 
regard. The blood and lymph circulations carry fluid to the tissues 
and away from them, but what the tissues will take up or give off 
rests with them. Only as these circulatory systems carry to the 
tissues substances which directly threaten their existence, or fail 
to remove such as the tissues have produced, which if allowed to 
accumulate will overcome them, only in so far are the circulatory 
systems masters of the tissues. 



PART FOUR 

ABSORPTION AND SECRETION IN THE COMPLEX 

ORGANISM 



PART FOUR 

ABSORPTION AND SECRETION IN THE COMPLEX 

ORGANISM 



I 

THE GENERAL PROBLEM 

The previous pages have dealt with the absorption and secre- 
tion of water from the point of view of the isolated cell, tissue, 
or organ. Our general conclusion has been that the tissues 
simply soak up a certain amount of water from the fluid medium 
in which they lie (the blood and lymph in the case of the higher 
animals) , and that this amount is determined by the state of the 
colloids found in the tissues. Before we can advantageously 
proceed with a discussion of the special aspects of oedema we 
need to consider this problem of absorption and secretion from 
the viewpoint of the organism as a whole. How can we utilize 
the teachings of colloid-chemistry in this direction? 

The absorption and secretion of water by a multicellular 
organism seems at first sight to be decidedly different from 
the absorption and secretion of water as observed in a single 
cell — say an ameba or a muscle cell. It is easy to think of an 
ameba as a spherical mass of colloid material saturated with 
water, and under changes in its physico-chemical surroundings 
or through direct changes in its own chemical composition so 
altering this colloid material as to make it take up or give off 
water. As I view it, this simple conception does constitute 
the heart of the entire problem of water absorption and secre- 
tion as observed in this animal. 

293 



294 



(EDEMA AND NEPHRITIS 



But in a multicellular organism biological facts confront 
us which do not at first seem to be interpretable on any such 
simple basis. In the mammal, for example, we find whole 
organs set apart, seemingly endowed with powers of absorption 
only, while others function seemingly only as secretory organs. 
It becomes hard, for example, to see just what relationship ex- 
ists between a mucosal cell of the small intestine concerned almost 
exclusively with an absorption of water from the lumen of the 
gut, or a kidney cell concerned equally exclusively with a secre- 
tion of urine, and the ameba or muscle cell which now absorbs 
and now secretes water either in response to its own physiological 
demands or under the conditions with which experimentally we 
are pleased to surround it. And yet on closer analysis the 
difference between the two is not so striking. 

First of all, we need to appreciate that the mucosal cell is 
an absorbing cell only so long as we look at it from the side of 
the lumen of the gut. If we regard it from the blood vessel side, 
the mucosal cell is a secreting cell, for what it absorbs from the 
gut it gives up to the blood. Similarly, the kidney cell is a 
secreting cell only because we usually look at it from the point 
of view of being a producer of urine — as a matter of fact, every- 
thing that goes to make up the normal urine was absorbed 
from the blood. But even if we look at the matter from the nar- 
rower point of view, the intestinal cells under certain circumstances 
become secreting cells in that they secrete substances into the 
lumen of the intestine; and according to the judgment of some 
authors, certain kidney cells may reabsorb materials that have 
been secreted by others. In essence, therefore, secretion and 
absorption in the higher animals is not different from absorp- 
tion and secretion as observed in an ameba or any isolated 
tissue cell. That which remains, therefore, to characterize absorp- 
tion and secretion in the higher animals is merely this, that under 
normal circumstances and viewed from the point of view of the organ- 
ism as a whole, absorption and secretion occur predominantly in 
one direction. What requires special analysis in the higher animals 
is, therefore, not absorption and secretion per se, but the condi- 
tions existing in the multicellular organism which make it 
possible for certain organs to act chiefly as absorbing systems, 
while others act predominantly as secreting systems. This 
is what creates all the problems that are conveniently grouped 



ABSORPTION, SECRETION— COMPLEX ORGANISM 295 



under the general heading of the special physiology of absorption 
and secretion, as observed in the higher animals. 

Let us see, first of all, if we cannot define in general terms 
what must be the conditions which lie at the bottom of this 
predominant functioning of certain cells and tissues in one 
direction, and this on the basis of our belief that the colloid con- 
stitution of the living cell is primarily responsible for the phenom- 
ena of water absorption and secretion by the cell. 

An ameba or an isolated cell or tissue derived from a higher 
animal and kept in a solution of any kind is surrounded by this 
solution on all sides. Could we imagine the chemical processes 
within these cells held in abeyance, then we see how they 
would after a time succeed in getting into a state of equilibrium 
with their surroundings. When such an equilibrium has been 
established, the cells neither absorb nor secrete water. Only 
as this equilibrium is disturbed, either through changes in the 
surroundings of these cells or through the specific chemical changes 
occurring in the cells, can we expect a renewed absorption or 
secretion. • 

Under quite different conditions do we find the individual 
cells of the multicellular organism existing in the intact living 
body. While in a certain sense the internal activities of the 
ameba may be compared with those of the individual cells mak- 
ing up, say the intestinal mucosa, and while there exists a certain 
analogy between the two in the fact that both are surrounded by a 
liquid medium, here the analogy stops. For while the ameba is sur- 
rounded on all sides by the same liquid medium, the cells of any 
of the absorptive or secretory organs, found for instance in a mammal, 
are through different portions of their cell protoplasm in contact 
with entirely different media. The cells constituting the intestinal 
mucous membrane, for example, are bathed on one side by intes- 
tinal contents; on the other by blood or lymph, or both together. 
Such cells, like any other absorptive or secretory cells similarly 
situated, find themselves, therefore, in the predicament of try- 
ing to get into equilibrium with as many different media as 
surround them. It is in trying to do this that all the phenomena 
that we call absorption and secretion in the higher animals are 
produced. 

It is in the attempt to get into equilibrium with the intestinal 
contents on the one side, and the blood on the other, that the 



296 



(EDEMA AND NEPHRITIS 



mucosal cell (better, the colloid membrane separating the intes- 
tinal contents from the blood), absorbs the intestinal contents 
and transfers them to the blood. How this is accomplished 
will now be discussed. 

II 

ON ABSORPTION 

1. General Remarks on the Physico-chemical Structure of an 
Absorbing System in the Complex Organism 

It follows as a necessary conclusion from our argument 
that in the resting state the body of a multicellular living organism 
— a mammal, for example — is built up of a system of different 
hydrophilic colloids saturated with water. To be counted in with 
the structures that make up this water-saturated colloid system and 
composing an integral part thereof, are the blood and the lymph. 
It may at first sight seem somewhat surprising that the blood and 
lymph are included, but the relation between the colloid and 
the water of fluid (hydrophilic) colloids, (sols), is identical with 
that of the relation between colloid and water in solid colloids 
(gels) such as fibrin. This identity is not only demanded by 
physico-chemical theory, but is proved experimentally by the 
work of Wolfgang Pauli and Hans Handovsky 1 on blood 
serum. 2 

That the entire mixture of solid and liquid colloid ma- 
terial constituting the organism is saturated with water is 
evidenced by the fact that we cannot make it, as a whole, take 
up any more water or give up any except as chemical changes 
are first produced in it which either increase or decrease the 
capacity of its colloids for holding water. In consequence, an 
organism not subject to any marked changes from without or 
within maintains a constant weight over long periods of time. 
We need but recall how all the secretions of a man undergoing 
absolute starvation drop to practically nothing, and how, on the 
other hand, the consumption of even enormous amounts of water 
by the normal individual does not lead to the development of 

1 Wolfgang Pauli and Hans Handovsky: Biochem. Zeitschr., 18, 340 
(1909). 

2 See page 145. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 297 



the slightest oedema. We are accustomed to say that the 
kidneys quickly rid the body of any excess of water. Just why 
this is done will be discussed shortly. The chemical changes 
capable of altering the hydration capacity of the body colloids 
may be of a character to affect the constitution of the entire mass 
that composes the body of a multicellular organism; or they may 
affect only smaller parts. In the former case we get either an 
absorption or a secretion of water by the organism as a whole; 
in the latter, only a limited or localized absorption or secretion 
of water by the parts involved. It is even possible for chemical 
changes to be going on in one part which lead to an absorption 
of water, while other changes are going on in another part which 
lead to a secretion of water. Thus, conditions are so arranged 
in the body under normal circumstances as to favor almost 
constantly the absorption of water from the gastro-intestinal 
tract, while at the same time they favor the secretion of the urine 
from the kidneys. 

An absorption system consists in essence of three parts or 
phases: 

(1) A material to be absorbed. 

(2) A membrane which does the absorbing, and 

(3) The blood or lymph into which the absorbed substance 
finally gets. 

In the case of the gastro-intestinal tract these general terms 
are synonymous with 

(1) The gastro-intestinal contents. 

(2) The gastro-intestinal mucosa with its specific cells and 
all their supporting structures, and 

(3) The blood and lymph. 

Let us consider for a moment their physico-chemical 
properties. 

(1) The gastro-intestinal contents from a chemical point 
of view represent a widely varying mixture. Expressed physico- 
chemically, however, they are a mixture of colloids and crys- 
talloids in water. In the process of digestion the colloids are 
for the most part converted by a series of chemical cleavages 
into crystalloids. Thus, the proteins are broken into amino- 
acids, the fats into fatty acid and alcohol (glycerin) , the car- 
bohydrates, when digestible, into the simple hexose sugars. In 
the end, the absorption of the gastro-intestinal contents becomes 



298 



(EDEMA AND NEPHRITIS 



really, therefore, the problem of the absorption of a watery solu- 
tion of various crystalloids. 

(2) The membrane through which the intestinal contents , 
are absorbed into the blood and lymph is made up of all the 
cellular and intercellular elements found between the gastro- 
intestinal contents on the one side and the circulating blood 
and lymph on the other. From a histological standpoint we 
know that this membrane is very different in different parts 
of the gastro-intestinal tube. With the different cells we must 
always in our considerations count in the intercellular substance 
that binds them together. From a physico-chemical stand- 
point this membrane is colloid in constitution. It is made up, 
in the main, of a mixture of various hydrophilic colloids. As 
a whole it is more or less solid in nature, like a leaf of gelatin 
soaked in water. But in no sense are the different portions 
of the gastro-intestinal tube made up of exactly the same colloid 
material, either in a chemical or a physical sense. We know 
this to be true because its different parts take up dyes, for ex- 
ample, with very different avidities when these are injected 
into the circulating blood. 

We have now to point out that while the colloid membranes 
with which we busy ourselves in the laboratory are made up of 
dead material, that separating the gastro4nte§tinal Contents 
from the blood and lymph is alive. This does not imply, how- 
ever, that we must at once become vitalists. It only means that 
it introduces a series of more or less independent chemical and 
physico-chemical reactions into our general problem of absorp- 
tion which demand additional care and study to analyze. 
The physico-chemical state of this living membrane is dependent 
upon the chemical changes that occur in the cells constituting 
this membrane, and these chemical changes are in turn intimately 
connected with the changes that occur in the blood supplying 
these cells. It is readily apparent, therefore, that the introduc- 
tion of a single variable into the circulation may upset the 
entire chemistry of the cells of the absorbing membrane, and 
so their physico-chemical state. This is why what looks like 
such a small change in our entire absorption system may be 
followed by a most profound, effect upon absorption. 

(3) The blood represents a mixture of various formed elements 
with a liquid menstruum. The formed elements are colloid 



ABSORPTION, SECRETION— COMPLEX ORGANISM 299 



bodies (nucleated and non-nucleated cells) which react toward 
changes in their environment (acid, alkalies, salts, non-elec- 
trolytes, etc.), in the very definite ways already described. The 
liquid portion of the blood (the plasma) is a liquid colloid mix- 
ture of various proteins. It behaves like a solution of gelatin, 
obeying laws identical with those governing the behavior of the 
more solid proteins which we have already discussed. Mixed 
with it are normally a number of different salts and varying 
amounts of different non-electrolytes. 

Absorption from the peritoneal cavity presents a problem 
fairly identical with that from the lumen of the gut. We need in 
the above paragraphs but to make the absorbing membrane 
consist of the peritoneal cells with their supporting elements 
instead of the mucosal cells with theirs. The blood and lymph 
remain the same, and the material to be absorbed from the 
peritoneal cavity may have under experimental conditions any 
composition we choose to give it. As absorption from the 
peritoneal cavity represents a somewhat simpler problem than 
absorption from the gut we shall consider it first. 

2. Absorption from the Peritoneal Cavity 1 

In view of the excellent running accounts of absorption 
that may be found by consulting R. Heidenhain, 2 Ernest H. 
Starling, 3 E. Waymouth Reid,* H. J. Hamburger, 5 E. Over- 
ton, 6 Otto Cohnheim, 7 or Rudolph Hober, 8 it is needless 
to attempt any detailed definition of the present status of our 

!See Martin H. Fischer: Kolloidchem. Beihefte, 2, 304 (1911). 

2 R. Heidenhain: Hermann's Handbuch der Physiologie, 5, Leipzig 
(1883); Pfliiger's Arch., 56, 579 (1894). 

3 E. H. Starling: Sehafer's Text-Book of Physiology, 1, 285, London 
and Edinburgh (1898); Oppenheimer's Handbuch der Biochemie, 3, 206, 
Jena (1909). 

4 E. Waymouth Reid: Sehafer's Text-Book of Physiology, 1, 261, London 
and Edinburgh (1898); Phil. Trans. Royal Soc, 192, 231 (1900); Journal 
Physiol., 26, 436 (1901). 

5 H. J. Hamburger: Osmotischer Druck und Ionenlehre, 2, 95, Wies- 
baden (1904). 

6 E. Overton: Nagel's Handbuch der Physiologie, 2, 774, Braunschweig 
(1907). 

7 O. Cohnheim: Nagel's Handbuch der Physiologie, 2,607, Braunschweig 
(1907). 

8 R. Hober: Koranyi-Richter, Physikalische Chemie und Medizin, 1, 295, 
Leipzig (1907). 



300 



OEDEMA AND NEPHRITIS 



knowledge of absorption. This is shown in a masterly way by 
these authors. Depending upon whom we consult we find sug- 
gested, as the forces active in this matter, variations in hydro- 
static pressure, filtration, or the two combined; diffusion and 
osmotic pressure, with modifications of both as determined by 
different media, different membranes and different solutions; 
imbibition; and when these physical forces are found wanting, 
then the " peculiar " forces of living matter are called upon 
for help. How unsatisfactory are all these explanations is 
clearly evidenced by the divergence of scientific opinion and the 
mutual criticism that finds expression in the individual writings 
of these authors, and this in spite of the fact that the experi- 
mental grounds upon which they base their opinions agree very 
well with each other. 

My own experiments referred to below were extremely 
simple in character, made purposely so in order to eliminate the 
many and great errors that creep into these absorption experiments 
as soon as anesthetics, operations, animal boards and elaborate 
pieces of apparatus are employed. Had it not been for the use 
of these, one might have contented himself with mere interpreta- 
tion of the experimental facts already found by previous authors. 
How some of these procedures affect absorption will be pointed 
out at the proper place. 

I used healthy guinea pigs which were kept on a liberal diet 
of timothy hay, corn and oats, with water ad libitum. In 
order to permit comparison with each other, the animals in 
each set of experiments were taken from the same cage and treated 
exactly alike. No anesthetic being necessary, none was given. 
The various solutions and the water, after warming to 38° C, 
were injected into the peritoneal cavity by means of a hypo- 
dermic needle. The animals were held only during the few 
moments necessary for the injection, after which they were allowed 
to run about in their cages. At the end of a specified time they 
were killed by a blow on the head, immediately opened, and the 
unabsorbed liquid contained in the peritoneal cavity aspirated, 
by means of a pump, into small flasks. The amount of fluid 
recovered was then measured. 

Let it be noted that what is discussed primarily in these 
pages is the absorption of water from the peritoneal cavity. 
A priori no one would be inclined to look upon the absorption 



ABSORPTION, SECRETION— COMPLEX ORGANISM 301 



of any solution as representing a single process, and yet, in practice, 
this is done and has been done constantly. On all sides we see 
discussed the absorption of a solution as such. The absorption 
of a solution represents the composite of the absorption of the solvent, 
and the absorption of every individual substance dissolved in that 
solvent. Absorption of solvent and absorption of dissolved 
substance may mutually affect each other (see below), but this 
does not make them identical, nor does it make the absorption 
of the solution a single process. Excellent experimenters have 
gone so far as to look upon the distribution of a dissolved sub- 
stance (such as a dye) in a tissue as evidence that the solvent 
in which that substance was originally dissolved was present 
there, or at least had passed that way. This is a most serious 
mistake. 

§ i 

When any liquid is injected into the peritoneal cavity and 
we find that after a time it has been absorbed, we know from 
anatomical considerations that it must have passed into the lymph 
and the blood streams after having traversed the cells and inter- 
cellular substance which originally separated these two circulat- 
ing fluids from the liquid that was injected. If we try to for- 
mulate the problem in terms of physical chemistry, then our 
purpose is to discover how the absorption of a solution that has 
any composition we may choose to give it, is accomplished by 
two colloid, circulating liquids (which, for the sake of brevity, 
we will regard as sols) that are separated from this solution by 
a solid colloid membrane (a gel). It is of interest for our further 
discussion first to call to mind which of these two liquid colloids 
plays the more important role in this absorption. As the per- 
itoneal cavity is usually regarded as an immense lymph space, 
one might on a priori grounds be inclined to look upon the 
lymphatic circulation as that chiefly concerned in absorption 
from this cavity. And yet that the lymph plays a subordinate 
part and the blood circulation the chief role is indicated by E. H. 
Starling and Tubby 's 1 finding that dyes appear in the urine 
after injection into the peritoneal cavity before the lymph 
coming from the thoracic duct shows any color; by the observ- 

1 Starling and Tubby: Journal of Physiol., 14, 140 (1894). Starling: 
Schafer's Text-Book of Physiology, 1, 304, London and Edinburgh (1898). 



302 



(EDEMA AND NEPHRITIS 



ation of Orlow, 1 who noticed no increase in lymph flow after 
intraperitoneal injections of salt solution; and by that of 
H. J. Hamburger 2 who found peritoneal absorption unim- 
paired after ligation of the thoracic duct. 

But, after the point is established that absorption from 
the peritoneal cavity is brought about chiefly through the agency 
of the blood, we have yet to say why this is the case. It is evident 
that the answer to this question bears both a quantitative and a 
qualitative element. In the higher animals the lymph circu- 
lation stands quantitatively far behind the circulation of the 
blood. Other things being equal, the blood would therefore 
absorb more than the lymph in proportion as the blood flow 
through a part exceeds quantitatively the lymph circulation 
through the same part. But chemical differences between the 
two play, to my mind, an equally important part. The total 
colloid content of the blood is higher than that of the lymph. 3 
But, beyond this, the blood suffers rapid temporary changes 
in chemical composition that the lymph does not. Chief among 
these are the quantitative variations in the content of oxygen 
and (especially) of carbonic acid as induced through respiration. 
Further changes in the composition of the blood are wrought 
through the diffusion of metabolic products into and out of it, as 
when the blood passes through the kidneys, active muscles, the 
liver, etc. While somewhat similar changes are induced in the 
lymph when this passes through various organs, the rapid varia- 
tions that we find in the blood are for obvious reasons lacking. 
But these more marked and rapid changes in the blood, com- 
bined with its more rapid circulation, mean at the same time 
more marked and rapid changes in the surroundings of the 
various tissue cells about which this circulating medium passes. 
The equilibrium with their surroundings which these cells endeavor 
to establish is therefore continually being disturbed because 
of these changes in their surroundings; and, so long as this 
happens, so long must the cells absorb. And hence the greater 

1 Orlow: Pfluger's Arch., 59, 170 (1895). 

2 H. J. Hamburger: Arch. f. (Anat. u.) Physiol., 281 (1895). 

3 Almost one-fourth of the blood is protein. Blood plasma contains to 
each 100 parts almost 9 parts of protein. Lymph contains 3.4 to 4.1 parts of 
protein. See C. Schmidt: Vierordt's Daten und Tabellen, 97, Jena (1888);, 
J. Munk and Rosenstein: Arch. f. Physiol., 376 (1890). 



ABSORPTION, SECRETION— COMPLEX ORGANISM 303 

importance of the blood circulation over the lymph circulation 
in this problem of absorption in the higher animals. 

. ." § 2 

Let us now turn to the problem of the absorption of water 
from the peritoneal cavity. When water is injected at body 
temperature into the peritoneal cavity of guinea pigs it is rapidly 
absorbed, as the following table shows: 



TABLE LXXXVII 



Guinea 
pig- 


Weight in 
grams. 


Amount of water 
injected in cc. 


Amount of fluid in cc. 
recovered after one hour. 


a 


413 


20.8 


5.4 


b 


535 


20.8 


5.4 


c 


544 


20.8 


4.8 


d 


460 


20.8 


4.9 



There is nothing new about this observation. Where we 
encounter difficulty is in saying why the water is absorbed. 
Against the generally accepted belief that water is under such 
circumstances absorbed because the osmotic pressure in the cells 
lining the peritoneum is higher than that of the distilled water, 
serious objections can be raised. We know that the peritoneum 
does not retain this water, but gives it up to the blood (chiefly) . 
On the osmotic basis this secretion into the blood could there- 
fore occur only because the blood has a higher osmotic concen- 
tration than the cell contents. As a matter of fact we know 
that body cells, lymph and blood have, to all intents and 
purposes, the same osmotic concentration. The still more seri- 
ous objection that this osmotic conception of water absorption 
ignores entirely the important part played by the intercellular 
substances need not be discussed here. That an injection of 
water into the peritoneum makes the cells here take up water 
because of an increased hydrostatic pressure directly induced by 
the injection, or aided by the contractions of the abdominal 
muscles, etc., is also scarcely tenable. The injection, first of 
all, does not appreciably increase the intra-abdominal pressure; 
and secondly, absorption occurs when the abdomen is opened, 
or in a dead animal (see below). 



304 



(EDEMA AND NEPHRITIS 



We have no difficulty in interpreting the absorption of water - 
from the peritoneal cavity as a colloid phenomenon. In order 
that the absorption of water may occur, the hydrophilic colloids of 
the peritoneum must only be unsaturated with water. But when 
we consider the fact that after a few cubic centimeters of water 
have been absobred from the peritoneal cavity, more may be 
absorbed if the injection is repeated and this almost without 
limit, then we have to conclude that under normal circumstances 
the tissues composing the peritoneum are constantly unsaturated 
with water. What we really have to discuss, therefore, are the 
conditions that combine to keep the colloids of these tissues 
unsaturated with water in the living animal. 

The first of these is the continuous production of acid 
(carbonic acid) in the tissues composing the peritoneum. In 
consequence of this the capacity of the tissues for holding 
water is increased, and they absorb it from any available source. 
If water is present in the peritoneal cavity they will take it up. 
But this would only lead to a swelling of the peritoneal tissues. 
As in this process an upper limit would soon be reached and 
absorption cease, this alone cannot lead to the continuous absorp- 
tion which is observed. A second variable must exist, and this 
is found in the circulation of the blood and the lymph. Through 
these the carbonic acid produced in the cells is constantly carried 
away. But to carry this away from the tissues is to reduce 
the capacity of the colloids of the peritoneum for holding water, 
which, in consequence, they now give up. As long as the circula- 
tion is maintained in a normal way absorption from the peritoneal 
cavity must therefore be continuous, for while the tissues of the peri- 
toneum are on the one side busy in absorbing water they are, on 
the other, busy in giving it up to the blood along with their carbonic 
acid. 

The blood also carries all water contained in it in com- 
bination with the colloids found in the blood. As the arterial 
blood, low in carbonic acid, (representing, as we have said, a 
liquid colloid solution saturated with water), enters the capillaries, 
there diffuses into it the carbonic acid that is being produced 
in the cells. Through this the capacity of the blood colloids 
to hold water is raised, they find themselves in an unsaturated 
condition, and so are able to absorb water from any available 
source. This could be water directly, though in the living body 



ABSORPTION, SECRETIQN— COMPLEX ORGANISM 305 

it means that the blood robs any tissue of its water that is holding 
it with less avidity than that represented by the colloids of the 
blood. In the case under discussion the blood absorbs water 
from the tissues composing the peritoneum. The peritoneum, in 
its turn, takes water from the peritoneal cavity, if any is present 
there. The now venous blood, with its higher water-content, 
passes to the lungs, where its carbonic acid escapes. When 
this happens the blood colloids are unable to. retain longer the 
water absorbed previously, and this becomes " free " in the 
blood. It is this " free " water that under normal conditions 
the kidney extracts from the blood, and, by a process the reverse 
of that which we have described for peritoneal absorption, 
secretes as urine, 1 To this question we return below, 

§ 3 

We can immediately apply an experimental test to this proc- 
ess of reasoning. If the blood coursing through the peritoneal 
tissues and the tissues themselves take up water only because 
their colloids are unsaturated with it, then clearly they should 
be unable to take it up when offered to them in their own form. 
In other words, they should be unable to absorb water from 
any " solution " in which all the water is held in combination 
with colloids in the same way as they hold it. As a matter of 
fact, they cannot, as proved by the following experiments with 
egg albumin, which represents a liquid in which all the water is 
bound to colloid material. 



TABLE LXXXVIII 



Guinea 
pig. 


Weight in 
grams. 


Amount and character of solu- 
tion injected. 


Amount of fluid 
in cc. recovered 
after one hour. 


a 


533 


20.8 cc. water 


5.4 


b 


537 


20 . 8 cc. white of egg (natural) 


18.4 


c 


555 


31 . 2 cc. water 


7.6 


d 


563 


31.2 cc. white of egg (natural) 


27.7 



Similar experiments with blood are described later. 2 It is 
because the water is thus united to colloid material that blood 
and lymph remain so long in the peritoneal cavity; in fact they 

1 See section on Secretion, p. 325. 

2 See page 740. 



306 



(EDEMA AND NEPHRITIS 



cannot be absorbed from here or from the intestinal tract until 
ferments or other conditions have first so affected the colloids 
that they yield up their water in a " free " form. 

§ 4 

The effect on water absorption when the same amount of 
differently concentrated sodium chlorid solutions are injected 
intraperitoneally instead of plain water is indicated in Table 
LXXXIX. 



TABLE LXXXIX 



Guinea 
pig. 


Weight in 
grams. 


Amount and character of solu- 
tion injected. 


Amount of fluid 
in cc. recovered 
after one hour. 


a 


417 


20.8 cc. water (control) 


5.4 


b 


397 


20.8 cc. m/12 NaCl 


11.8 


c 


419 


20.8 cc. m/8 NaCl 


13.0 


d 


488 


20.8 cc. m/6 NaCl 


14.6 


e 


445 


20.8 cc. m/4 NaCl 


19.9 



The interpretation of these findings is about as follows: 
When, in place of pure water, a sodium chlorid solution is 
introduced intraperitoneally we may assume that the water 
of this solution tries to diffuse into the cells just as though the 
salt were not there. But, at the same time that this is occurring, 
the salt is also diffusing into the peritoneum. Just why this 
happens is discussed below. But the presence of the salt in the 
colloids of the peritoneal tissues will make these tend to give 
up water. The salts will, therefore, tend to counteract the 
effect of the carbonic acid in the cells. The normal fall which 
tends to make the water move from the peritoneal side of the 
peritoneal absorbing membrane to the vascular side will now be 
counteracted by one occurring in the opposite direction. The 
normal streaming of water which tends to make for an absorption 
from the peritoneum will be met by a counterstream which 
tends to make for a secretion from this structure. The end 
result, so far as absorption of water is concerned, will represent 
the algebraic sum of the two. If this second stream is not a 
great one, there will be only a slight reduction in the rapidity 
with which the water is absorbed. This is what happens with 
the dilute salt solution. But, as the concentration of the salt 



ABSORPTION, SECRETION— COMPLEX ORGANISM 307 



increases, this counter-current must become more and more 
manifest, so that, as in the last experiment (e) of Table LXXXIX, 
practically no absorption (of water) occurs within the time limits 
set for the experiment. 

§ 5 

In equimolar concentrations different salts affect to very 
unequal degrees the absorption of water by colloids swelling 
in the presence of an acid. So also, and in the same general order, 
do they affect the absorption of water by the peritoneum. 



TABLE XC 



Guinea 
pig- 


Weight in 
grams. 


Amount and character of solu- 
tion injected. 


Amount of fluid 
in cc. recovered 
after one hour. 


a 


643 


20.8 cc. m/8 sodium chlorid 


7.0 


b 


594 


20.8 cc. m/8 sodium acetate 


10.0 


c 


551 


20.8 cc. m/8 sodium nitrate 


12.6 


d 


409 


20.8 cc. m/8 sodium sulphate 


20.0 


e 


496 


20.8 cc. m/8 sodium citrate 


23.4 


f 


492 


20.8 cc. m/8 disodium phosphate 


25.6 



TABLE XCI 



Guinea 
pig- 


Weight in 
grams. 


Amount and character of solu- 
tion injected 


Amount of fluid 
in cc. recovered 
after one hour. 


a 
b 
c 
d 

e 
f 


h 


343 
335 
322 
290 

355 
354 
363 

386 


20.8 cc. m/8 potassium iodid 
20.8 cc. m/8 potassium bromid 
20.8 cc. m/8 potassium chlorid 
20.8 cc. m/8 potassium sulpho- 
cyanate 

20.8 cc. m/8 potassium nitrate 
20.8 cc. m/8 potassium acetate 
20.8 cc. m/8 potassium tartrate 

(died 40 minutes after injection) 
20.8 cc. m/8 potassium oitrate 

(died 15 minutes after injection) 


3.4 
8.8 
11.0 
13.4 

13.4 
16.8 
18.9 

20.5 


TABLE XCII 


Guinea 
Pig- 


Weight in 
grams. 


Amount and character of solu- 
tion injected. 


Amount of fluid 
in cc. recovered 
after one hour. 


a 
b 
c 
d 
e 


452 
396 
484 
476 
502 


20.8 cc. m/8 potassium chlorid 
20.8 cc. m/8 ammonium chlorid 
20.8 cc. m/8 magnesium chlorid 
20.8 cc. m/8 calcium chlorid 
20 . 8 cc. m/8 strontium chlorid 


12.8 
13.7 
19.4 
24.2 
24.4 



308 



(EDEMA AND NEPHRITIS 



As Tables XC, XCI, and XCII, show clearly, every one 
of the salts employed markedly retards the absorption of water 
from the peritoneal cavity. This harmonizes entirely with the 
fact that the presence of every salt inhibits the absorption of 
water by such a hydrophilic colloid as fibrin, gelatin or serum 
albumin which is swelling in the presence of an acid. But the 
parallelism between the two processes is even closer than this. 
We note in Table XC, for example, where the effects of equimolar 
solutions of sodium salts are compared, that the sulphate, citrate 
and phosphate have an effect far above that of the chlorid, acetate 
or nitrate in preventing absorption. In Table XCI, where the 
effects of a series of potassium salts are compared, the order of 
the acid radicals is again the familiar one observed in studies on 
pure protein colloids. Table XCII brings out the same fact for 
a series of different basic radicals. That the results should be so 
nearly identical with the effects of various salts on pure colloids 
is really somewhat surprising when we remember that in such 
experiments as these one is compelled to work with a con- 
siderable experimental error, arising from the fact that in each of 
these series several animals are used, that we cannot control the 
amount of water consumed by them just before being used, that 
we cannot escape the specific poisonous effects exerted by the dif- 
ferent salts employed, etc. Nevertheless the experimental 
results are point for point almost identical with the findings on 
pure colloids. This indicates to my mind how predominant is 
the colloid element in this problem of absorption. 



§ 6 

As compared with the effect of electrolytes, various non- 
electrolytes affect the absorption of water by colloids in the 
presence of any acid only slightly. Table XCIII gives the 
results obtained when solutions of various non-electrolytes in 
concentrations osmotically about equivalent to the solutions 
of the various salts used above, are injected intraperitoneally : 

It is clear from this table that ethyl and methyl alcohols 
do not delay the absorption of water from the peritoneal cavity. 
On the other hand, glycerin and the two sugars used produce 
a decided inhibition. The sugars even produce a secretion of 



ABSORPTION, SECRETION— COMPLEX ORGANISM 309 



fluid. The effects again agree with the findings on pure colloids 
where only the last-named produce in the higher concentrations 
a dehydration. 



TABLE XCIII 



Guinea 
pig. 


Weight in 
grams 


Amount and character of solu- 
tion injected. 


Amount of fluid 
in cc. recovered 
after one hour. 


o 


425 


20.8 cc. m/4 ethyl alcohol 


5.8 


b 


434 


20.8 cc. m/4 methyl alcohol 


2.1 


c 


464 


20.8 cc. water (control) 


5.6 


d 


- 583 


20. 8 cc. m/4 urea 


11.7 


e 


569 


20.8 cc. m/4 glycerin 


18.2 


f 


687 


20.8 cc. m/4 glycerin 


17.4 





521 


20.8 cc. m/4 cane sugar 


25.7 


h 


725 


20.8 cc. m/4 cane sugar 


27.0 


i 


522 


20.8 cc. m/4 dextrose 


26.3 


3 


710 


20.8 cc. m/4 dextrose 


29.0 

i 



§ v 

Both alkalies and acids when injected intraperitoneally 
delay the absorption of water, as indicated in the following table: 



TABLE XCIV 



Guinea 
pig- 


Weight in 
grams. 


Amount and character of solu- 
tion injected. 


Amount of fluid 
in cc. recovered 
after one hour. 


a 


544 


20.8 cc. water (control) 


4.7 


b 


545 


20.8 cc. n/100 NaOH 


6.2 


c 


543 


20.8 cc. n/50 NaOH 


11.0 


d 


568 


20.8 cc. n/25 NaOH 


10.6 


e 


460 


20.8 cc. water (control) 


4.8 


/ 


460 


20.8 cc. n/100 HC1 


7.4 


Q 


447 


20.8 cc. n/50 HC1 


12.4 


h 


450 


20.8 cc. n/33 HC1 


12.0 



In explanation of these results the following is offered. In 
the concentrations employed both acids and alkalies produce 
an excessive swelling of the peritoneal tissues. This excessive 
swelling delays absorption, not alone by occluding the lumina 
of the capillaries supplying the peritoneum and so decreas- 
ing the absolute blood flow through these tissues, but by so 
increasing the avidity of the peritoneal tissues for water that 
the blood passing through them is not enabled to take the water 
away from them with its usual ease. 



310 



(EDEMA AND NEPHRITIS 



§ 8 

Table XCV shows how water and various salt solutions 
are absorbed from the peritoneal cavities of dead animals. The 
guinea pigs were killed by a blow on the head, and injected sub- 
sequently in the same way as in the experiments with living 
animals. After injection, the animals were turned about a few 
times to allow the liquids to spread through the peritoneal cavity, 
and were then laid quietly on their bellies for one-half hour, 
after which they were turned on their backs for one-half hour. 



TABLE XCV 



Guinea 
pig- 


Hours 
dead. 


Weight- 
in grams. 


Amount and character of 
solution injected. 


Amount of fluid 
recovered in 
cc. after 
1 hour. 


Recovered from 
second pouring 
in of 20.8 cc. 
water after 
1 hour. 


a 


just dead 


331 


20.8 cc. water 


7.6 




b 


just dead 


396 


20. 8 cc. water 


9.0 




c 


1.00 


333 


20. 8 cc. water 


9.4 


15.3 


d 


2.30 


351 


20.8 cc. water 


9.3 


15.0 


e 


7.30 


395 


20.8 cc. water 


8.0 




f 


24.00 


375 


20. 8 cc. water 


12.5 




9 


48.00 


353 


20.8 cc. water 


17.0 




h 


0.15 


267 


20.8 cc. m/8 NaCl 


13.2 




i 


0.15 


295 


20.8 cc. m/8 Na 2 S04 


10.6 1 




3 


0.15 


299 


20.8 cc. m/8 sodium citrate 


11.4 i 





1 A part of the peritoneal fluid was accidentally lost. 



The table shows that water is readily absorbed from the 
peritoneal cavities of dead animals. How is the result to be 
explained? The answer is not essentially different from that 
given for the living animal. An acid production in the tissues 
is again responsible for increasing the capacity of the tissue col- 
loids for holding water. Only, while we attributed this to car- 
bonic acid in the living animal, we can attribute it in the dead 
animal not only to this acid, but in addition to lactic and the 
other acids that we know are produced postmortem. The longer 
an animal is dead, the higher we may assume becomes the con- 
centration of the acids in the various tissues. On this basis 
we might expect a progressively greater absorption of water 
with every increase in the length of time that an animal is dead. 
But this could hold only within certain limits, for in pure colloids 
we know that with a progressive increase in acid concentration 



ABSORPTION, SECRETION— COMPLEX ORGANISM 311 



the absorption of water increases only up to a certain point, 
after which a decreased absorption is noted. The same is evident 
in Table XCV, where animals long dead (/ and g), show a decidedly 
lower absorption of water than animals dead only a short 
time. 

As is sufficiently well indicated by the results obtained with 
animals, h, i and j, various salts retard the absorption of water 
from the peritoneal cavity of dead animals as they do. in living 
animals, and, we would add, for the same reason. 

3. Absorption from the Gastro-intestinal Tract 

The foregoing paragraphs, which show that the same con- 
ditions that retard the absorption of water by such hydrophilic 
colloid as fibrin or gelatin, retard in almost identical fashion 
the absorption of water from the peritoneal cavity, prove, it seems 
to me, that the two processes are in essence the same. What is 
next in order is to compare this process of peritoneal absorption 
with the processes of absorption as observed in other regions of 
the mammalian organism to see if the conclusions drawn regard- 
ing absorption as observed in the peritoneal cavity cannot be 
extended to cover at least some of these. Of chief interest in 
this connection, because of its physiological importance, is 
absorption from the intestinal tract. 

To anyone conversant with the wealth of experimental 
data on alimentary absorption that has been accumulated by 
Voit and Bauer, 1 R. Heidenhain, 2 Franz Hofmeister, 3 
H. J. Hamburger, 4 R. Hober, 5 G. B. Wallace and A. R. 
Cushny, 6 Otto Cohnheim, 7 E. Waymouth Reid 8 and G. 
Kovesi, 9 the following are familiar facts: 

1 Voit and Bauer: Zeitschr. f. Biologie, 5, 536 (1869). 

2 R. Heidenhain: Pfiiiger's Arch., 56, 579 (1894); 62, 331 (1896). 

3 Franz Hofmeister: Arch. f. exp. Path. u. Pharm., 28, 210 (1891). 

4 H. J. Hamburger: Osmotischer Druck und Ionenlehre, 2, 168, Wies- 
baden (1904), where references to his earlier papers will be found. 

5 Rudolph Hober: Pfiiiger's Arch, from 70 on; see his many papers 
during the years 1898 to date. 

*G. B. Wallace and A. R. Cushny: Am. Journal of Physiol., 1, 411 
(1898); Pfiiiger's Arch., 77, 202 (1899). 

7 Otto Cohnheim: Zeitschr. f. Biol., 36, 129 (1897); 37, 443 (1899). 

8 E. Waymouth Reid: Journal of Physiol., 21, 85 (1897); 22, 56 (1898); 
26, 427 (1901). 

»G. Kovesi: Centralbl. f. Physiol., 11, 553 (1897). 



312 



(EDEMA AND NEPHRITIS 



When water is introduced into a segment of intestine it is 
rapidly absorbed. All salt solutions, so far as the water in them 
is concerned, are absorbed less rapidly than the pure water. 
The concentration of the salt solution is an important factor 
in this phenomenon. When sodium chlorid solutions of different 
concentrations are compared, they are found to be absorbed 
the more slowly the higher the concentration of the salt. If 
sufficiently strong solutions are employed there may first result 
a pouring out of liquid into the lumen of the gut, so that the 
solution becomes diluted, after which it is slowly absorbed. 

When the absorption of equimolar (or better, osmotically 
equivalent) solutions of different salts is studied, it is found 
that these are absorbed at very different rates. The effect of 
any salt in a solution upon the absorption of water from that 
solution may be thus stated: With a given base, the acid 
radicals arrange themselves in the following order, where that 
which retards least is given first: 

Chlorid, bromid, iodid, nitrate, sulphate, phosphate. 

With a given acid, the order of the basic radicals is as 
follows (R. Hober), that least effective in preventing absorp- 
tion being given first: 

Potassium, sodium, calcium, magnesium, barium. 

It is easy to see that the order of the various salts is 
practically identical with that found above in the experiments 
on peritoneal absorption. The position of the acetate, tar- 
trate and citrate, not given in the above lists, can be deter- 
mined by consulting the tables of Wallace and Cushny, when 
it is found that they occupy a place in the absorption of water 
from the gut which is the same as that occupied by them in the 
case of peritoneal absorption. 

With any of these salts, as with ordinary sodium chlorid, 
the delay in the absorption of the water grows with the con- 
centration of the salt. A point is finally reached where such 
water as is introduced into the intestine is not only not 
absorbed, but water is secreted into the gastro-intestinal tract. 
This concentration point lies high in the case of sodium chlorid, 
sodium bromid, etc., but very low in the case of sodium sul- 



ABSORPTION, SECRETION— COMPLEX ORGANISM 313 



phate, phosphate, tartrate, citrate, etc. This is one of the chief 
reasons why the last named are known as " saline cathartics." 
Point for point, therefore, the absorption and secretion of water 
by the gut is identical with the absorption and secretion of water 
by the peritoneum, and both are comparable to the absorption and 
secretion of water by simple protein colloids when placed in like 
surroundings. 

The identity of the processes of absorption from the per- 
itoneal cavity and from the intestinal lumen goes even further. 
The rapid absorption of aqueous solutions of various alcohols 
from the intestinal tract shows that these non-electrolytes do 
not interfere with the absorption of water even when present 
in concentrations osmotically equivalent to those of the active 
salts. Sugar solutions and glycerin also behave in the intestinal 
tract, so far as the absorption of water from their solutions is 
concerned, as they do when introduced intraperitoneally. The 
slow absorption of water, or, in response to the introduction of a 
solution of sufficiently high concentration, the actual secretion 
of water into the gut, is evidenced not only by direct experiment, 
but by everyday clinical experience. Are not the sugars, when 
consumed in any considerable quantities, capable of producing 
watery stools (independently of any previous fermentation with 
the production of organic acids), and do not glycerin enemas 
produce the same secretion of water into the bowel that results 
when enemas containing any of the saline cathartics are employed? 

We have interesting parallels also of the peritoneal experiments 
which showed that water when united to a hydrophilic colloid is 
incapable of being absorbed without first being freed. Thus, 
protein solutions (such as egg white, blood, or blood serum) 
are not absorbed from the intestinal tract unless proteolytic fer- 
ments are present which, by acting on the proteins chemically 
destroy their markedly (hydrophilic) colloid character, and so 
liberate the water held by them. In this way also can we under- 
stand the behavior of cellulose and, especially, agar-agar in 
preventing constipation. One of the commonest causes of con- 
stipation resides in the too perfect absorption of water from the 
gastro-intestinal contents. It is a time-honored custom to suggest 
the addition of vegetables to the diet of such individuals. In 
addition to the action of the salts (citrates, tartrates, etc.) 
obtained from vegetables and the effects of the production 



314 



(EDEMA AND NEPHRITIS 



(through fermentation) of certain organic acids in the bowel 
which alone tend to prevent a too great absorption of water from 
the gastro-intestinal contents, the high cellulose content of 
such a diet (that is to say, its high hydrophilic colloid content) 
makes it impossible for the mucosa to get the water out of it. 
Since cellulose is not changed (except very slightly by certain 
bacteria) in its passage through the gastro-intestinal tract, it 
retains all the water with which it was saturated before being 
consumed, or with which it saturates itself in its course through 
the alimentary tract. The same explanation holds for agar- 
agar or the feeding of any of the Japanese sea weeds from which 
this is prepared. Agar-agar is a hydrophilic colloid incapable 
of being affected chemically in its passage through the gastro- 
intestinal tract (L. B. Mendel and Saiki), and so any water that 
it may have absorbed before being swallowed, or may absorb in 
the gastro-intestinal tract, is retained. In this way the inspissa- 
tion of the gastro-intestinal contents (and so the constipation) 
is prevented. 

These paragraphs suffice to show that the colloid-chemical 
theory is adequate to explain the qualitative aspects of water 
absorption in the complex organism. It remains to show that 
it is also adequate from a quantitative point of view. This is 
easily done. The anatomical and physiological conditions exist- 
ing normally in the body tend to keep the colloids of the gastro- 
intestinal tract and of the blood and lymph streams passing through 
it in an unsaturated condition so far as water is concerned, while 
the reverse conditions hold for any secreting organ such as the kidney. 

The mouth and esophagus play practically no role in the 
absorption of water. The stomach, according to von Mering's 
experiments, also takes but little if any part in the absorption 
of water. The small and large intestine are the absorptive organs 
for this substance par excellence. The stomach is richly supplied 
with arterial blood. The small and large intestine are also 
generously supplied, but not as generously as the stomach. The 
separate branches of the mesenteric arteries which go to supply 
the villi occupy a fairly central position in this structure and break 
up into a capillary network which lies close under the intestinal 
epithelium. As clearly evidenced by the dark color of the portal 
blood, and direct gas analysis, the blood returning from the 
intestine is intensely venous (poor in oxygen and rich in car- 



ABSORPTION, SECRETION— COMPLEX ORGANISM 315 



bonic acid). The experiments of von Limbeck, Gurber, and 
Hamburger 1 show that under the influence of such an increase 
in carbonic acid concentration as exists normally in venous blood 
over arterial blood the red and white corpuscles absorb an amount 
of water which easily amounts to from 5 to over 15 per cent 2 
of their volume in arterial blood. If we use only the lower of 
these values and ignore entirely the water-carrying power of 
the colloids contained in the plasma, a little calculation shows 
that every liter of blood passing through the intestinal tract 
is capable of absorbing 17.5 cc. of water, for the corpuscles when 
moist make up, in round numbers, about 35 per cent of the blood. 
Even these values, which have been chosen as low as possible, 
easily suffice to account for the absorption of great amounts of 
water from the gastro-intestinal tract, 

4. Historical and Critical Remarks on the Theory of Absorption. 
Peritoneal and Alimentary Absorption of Dissolved Sub- 
stances. 

Let us now consider for a moment the explanations of absorp- 
tion that have been given by other authors, and select from them 
not only the elements which we ourselves think to be correct, 
but point out, with the help of a few examples, how certain 
experiments which have long stood as the bulwark of " physiolog- 
ical " or " vitalistic " interpretations of certain life phenomena 
are easily explained on the colloid basis, and how others long 
held to support different theories of absorption fall in with the 
colloid one. 

1 H. J. Hamburger: Osmotischer Druck u. Ionenlehre, 1, 291, Wiesbaden, 
(1902); ibid., 1, 404 (1902). 

2 These figures are nearly doubled if instead of comparing the sizes of the 
corpuscles in arterial and in ordinary venous blood the sizes in arterial and 
passively congested venous blood are compared. In other words, the same 
circumstances that make the passively congested organ become cedematous 
make the corpuscles in the blood become " cedematous," and since the 
(colloid) plasma also " swells," venous blood or " passively congested " blood 
is, if water is available, richer in water than normal arterial blood. The 
blood is " hydremic," but this hydremia is not the cause of an oedema; it 
is an oedema itself, and an expression of the same factors which make the 
more solid tissues "cedematous." 



316 



(EDEMA AND NEPHRITIS 



§ 1 

For half a century various authors have thought that filtra- 
tion plays an important part in the absorption of liquids. Accord- 
ing to definition, filtration represents the passage of a liquid 
through a separating membrane of some sort in consequence 
of differences in hydrostatic pressure. On this basis it has 
been held that a liquid is forced from the lumen of the gut or 
from the peritoneal cavity into the blood because of a pressure 
within the gut or peritoneal cavity (produced through gas or 
the action of muscles of various kinds) which exceeds the pres- 
sure in the blood. Such a belief has been supported by the 
experiments of Leubuscher and H. J. Hamburger, 1 who found 
that with an increase in intra-intestinal or intra-abdominal 
pressure there resulted an increase in absorption, at least up to a 
certain point. Without for the moment questioning the correct- 
ness of the experimental finding itself (a serious error enters into 
it) we know that such an intra-intestinal or intra-abdominal 
pressure is not necessary for absorption. E. Waymouth Reid 2 
found absorption (of water) to occur from the intestine of the 
dog, when the pressure within the gut was decidedly lower 
than that in the mesenteric veins, and Hamburger himself 
describes experiments in which he observed a ready absorption 
of water from the peritoneal cavity when the abdomen was opened 
or when the animal was dead. 

After what has been said above regarding water absorption 
as a colloid phenomenon these findings are entirely to be expected. 
What is needed is an interpretation of Leubuscher and Ham- 
burger's experiments with changes in pressure. Leubuscher's 
result has been explained by saying that through increased intra- 
intestinal pressure the folds of the intestinal mucosa are smoothed 
out, and so an increased surface of gut is rendered available for 
absorption. But this explanation has not been accepted as 
complete by Hamburger, who found an increased absorption 
from the gut with every increase in pressure up to a certain point, 
even after surrounding the intestine with a wire cage which 
prevented its unfolding. In explanation of Hamburger's 
result, I would agree with the view that with the first increase 

1 H. J. Hamburger: Osmotischer Druck und Ionenlehre, 2, 176, Wies- 
baden (1904). 

2 E. Waymouth Reid: Phil. Trans. Royal Soc, 192, 231 (1900), 



ABSORPTION, SECRETION— COMPLEX ORGANISM 317 



in pressure the flow of blood out of the veins is favored. In 
consequence of this the blood flow through the gut is favored 
and so the conditions for absorption. With a further increase 
in pressure, the blood vessels are compressed, and now the blood 
flow is diminished, in consequence of which a decrease is absorp- 
tion is observed, as Hamburger found. 

Consideration of the available experimental facts must there- 
fore make one largely unwilling to look upon filtration as a factor 
of any large importance for the passage of liquid from the peri- 
toneal cavity or the lumen of the gastro-intestinal tract into the 
blood. But while the absorption of water may occur without 
the existence of pressure differences this does not say, of course, 
that such pressure differences when they do arise under certain 
circumstances may not then be of some physiological importance. 
But to my mind, this can never be great. The final answer 
to the problem, however, depends upon what is the structure 
(the porosity) of the colloid membranes through which the 
water is supposed to be forced and the differences in pressure 
available in the body for a filtration. To the discussion of these 
points we return later. 1 

§ 2 

The question of osmotic pressure (even as modified through the 
conception that the surface layer of the cells is lipoid in character) 
in the problem of water absorption from the peritoneal cavity or 
the gut needs no special discussion — its inadequacy to explain 
the phenomena of absorption as observed here is admitted on 
all sides. That it is still adhered to, no doubt depends on the 
fact that we have had nothing more adequate to substitute 
for it; and any number of biological workers have been unwilling 
to believe that a present inability to explain on a purely physico- 
chemical basis all the phenomena of absorption (or secretion) 
presages that such will never be forthcoming, and that, in con- 
sequence, support is lent " physiological " or " vitalistic " 
conceptions of the process. It seems to me that on the basis 
of what has been said in these pages and in my previous papers, 
we are now in a position where we not only may, but must, dis- 
card the osmotic conception of cell behavior so far as water 

1 See pages 371 and 380. 



318 



(EDEMA AND NEPHRITIS 



absorption is concerned. We must also discard it so?ar as the 
absorption of dissolved substances is concerned. 

As already noted, if cells were surrounded by semi-permeable 
films, as demanded by the osmotic theory, dissolved substances 
could neither get into nor out of them. Yet both must be pos- 
sible, as well as the movement of water into and out of cells, 
otherwise their life would cease. Dissolved susbtances get 
into and out of cells by diffusion. The role of this factor has 
been recognized and discussed as active in the process of absorp- 
tion since the days of Carl Ludwig. R. Heidenhain succeeded 
in minimizing its importance in the analysis of the whole prob- 
lem by showing that an absorbed fluid (or a secretion) usually 
differs in quantitative composition from the source from which 
it was derived. On this is based his belief in the selective 
" physiological " character of absorption (and secretion). There 
is nothing surprising about these phenomena to us. We expect 
them, in fact. As has been said, a solution is never absorbed 
(or secreted) as such. Whenever a solution is seen to be absorbed 
(or secreted), we are observing the composite of the absorption 
(or the secretion) of the solvent plus the absorption (or secretion) 
of each individual substance dissolved in that solvent. Wlien 
any solution is introduced into the intestine, for example, each 
one of the dissolved substances diffuses into the wall of the intes- 
tine until an equilibrium is established in the distribution of each 
of these substances between the (liquid) phase represented by 
the solution and the more solid phase represented by the (colloid) 
intestinal wall. Similarly, every substance present in the 
intestinal wall tends to diffuse out into the solution to the estab- 
lishment of an equilibrium. 

In biological material it has been very generally assumed 
that the distribution of dissolved substances between two such 
phases should attain equilibrium when the concentration of any 
dissolved substance is the same in both. Such an a priori con- 
clusion is entirely unjustified. We deal in this problem with the 
distribution of a dissolved substance between water and a colloid, 
and, as we know from the facts now available on this subject, 
equilibrium may be reached when the dissolved substance is 
contained in less, the same, or a higher concentration in the col- 
loid than in the solution surrounding it. 1 

1 Franz Hofmeister: Arch. f. exp. Path. u. Pharm., 27, 395 (1890); 
28, 210 (1891). 



ABSORPTION, SECRETION— COMPLEX ORGANISM 319 



Now, while the absorptive membrane is trying to get into 
equilibrium with the solution to be absorbed on the one side, 
it is also trying to get into equilibrium with the blood on the 
other. The whole absorptive system consists of the three 
phases (the material to be absorbed, the colloid absorbing 
membrane, the liquid colloid blood and lymph) already discussed, 
and the problem of the " selective " absorption of the dissolved 
substance is the problem of the agencies concerned in establishing 
an equilibrium between all the various dissolved substances in 
these three phases. The factors of greatest importance in such 
a problem are the character of the various colloids concerned, 
and their physico-chemical state as determined through the 
presence of acids, alkalies, salts and various non-electrolytes; 
the nature of the dissolved substance to be absorbed, as its rate 
of diffusion; the presence or absence of lipoids in the colloid, 
absorbing membrane and in the blood, etc. In other words, 
the laws of adsorption, of partition, and of chemical combination 
are all at work. To the process of simple diffusion in this matter 
of absorption (or secretion) become added therefore a series of 
secondary phenomena that obscure its purity. 

To illustrate what has been said, let us try to follow the 
relatively simple process of the absorption of a strong (so-called 
hypertonic) sodium chlorid solution when this is introduced 
into the peritoneal cavity, or into the intestine. Both the water 
and the salt begin immediately to diffuse into the absorbing 
membrane. As this progresses, the concentration of the sodium 
chlorid in the absorbing membrane rises. This rise in con- 
centration so affects the colloids of the absorbing membrane 
that they stop taking up water, or, if sufficiently strong, an 
actual secretion of water into the peritoneal cavity or the gut 
may follow. While this is occurring, an equilibrium is tending 
to be established between the concentration of the sodium 
chlorid in the solution undergoing absorption and the sodium 
chlorid in the absorbing membrane. But this is never attained 
under normal circumstances, because the salt in the absorbing 
membrane is at the same time trying to get into equilibrium 
with the sodium chlorid in the blood. Now, since this is circu- 
lating, it is evident that the equilibrium is constantly being 
broken down toward the side of the blood. In consequence 
of this, more and more salt must move over into the blood (be 
absorbed). But, as this occurs, the state of the colloids of the 



320 



(EDEMA AND NEPHRITIS 



absorbing membrane again returns to a more " normal " one 
and so the absorption of water, which could not occur before, 
can again take place. 

With a dilute (a hypotonic) solution of sodium chlorid the 
water does not meet with so great a resistance to absorption, 
and it is, therefore, possible for the dilute salt solution to become 
more and more concentrated as the water is (the more rapidly 
of the two) absorbed from it. 

Even salt solutions isotonic or isosmotic with the blood must 
be absorbed. Though such a solution cannot be absorbed 
on the osmotic basis because no differences in osmotic pressure 
exist to make the water move, there is no difficulty in interpreting 
what happens on the colloid basis. Let the colloids of the absorb- 
ing membrane take a little water from the isotonic solution 
and salt must quickly follow, for now its concentration is no 
longer in equilibrium with that of the sodium chlorid in the absorb- 
ing colloid membrane. Then more water goes in, and then more 
salt, until all is absorbed. Or we could start the absorption 
by having a little salt go in first and then the water, etc., for if 
the truth be told we do not yet know just what, concentration 
characterizes the " isotonic " solution, nor shall we until the 
colloid constitution of living matter has been adequately taken 
into account. 

Finally, on the basis of these conceptions of absorption, we 
experience no difficulty in understanding why any solution 
remaining for longer periods in the peritoneal cavity or in the 
intestine (while being u absorbed ") has substances found in the 
blood or tissues appear in it which it did not originally contain. 
As dissolved substances diffuse out of a solution undergoing 
absorption into the absorbing membrane until an equilibrium 
is established, just so, of course, must the substances contained 
in the absorbing membrane tend to diffuse into the solution. 
It has been generally held that this diffusion of salts (and 
other substances) out of an absorbing membrane into a 
solution that is being absorbed constitutes " an attempt to 
establish osmotic equilibrium between the two." As a matter 
of fact such a conclusion is premature if nothing more. We 
do not yet know all the factors involved in determining the 
point of equilibrium in the body, in the distribution of the various 
dissolved substances between the phases concerned. One thing, 



ABSORPTION, SECRETION— COMPLEX ORGANISM 321 

however, is certain and that is that the final equilibrium is not 
a simple osmotic equilibrium. This is clearly enough evidenced 
not alone by the well-known fact that the physiological behavior 
of different salts, in this process of absorption, for example, 
bears no relation to their osmotic concentration, but by the 
further fact that the distribution of most dissolved substances 
between a colloid and a solvent is practically never the same 
in both. The " selective " character of absorption depends upon 
the fact that the absorption of water in the living organism is a 
process entirely separate from the absorption of dissolved substances. 
Of the latter each moves at its own rate, and is influenced in its 
movement by factors that may not affect others in the sa?ne way 
or to the same degree. A dissolved substance may actually be 
absorbed while water is being secreted, and vice versa. Thus, to 
produce catharsis a saline cathartic diffuses into the wall of the 
gut (is absorbed) while water is being given off (is being 
secreted); and salts diffuse into the distilled water introduced 
into the bowel while this is being taken up by the mucous 
membrane. Such facts would be impossible of explanation if 
the cells had " osmotic," " lipoid," or similarly constituted 
" membranes " about them. If what is here written will be 
kept in mind the " selective " character of absorption ceases 
to produce astonishment — it would be more strange were it 
not selective. 

§ 3 

The workers in physiology and experimental medicine, who 
have called attention to the u secretory " and " physiological " 
activities of absorbing (and secreting) membranes and to the 
" physiological driving force " 1 situated in them, are deserving 
of blame or praise depending upon whether they used these 
words in the despairing attitude of those biological workers 
who believe that life phenomena will never be interpretable 
solely in the terms of the physical sciences, or as convenient 
heads under which to group certain of the phenomena of absorp- 
tion and secretion which could not be so analyzed at the time 
they prosecuted their scientific studies. But the necessity of 
retaining these terms, even in the latter sense, may now largely 

1 " Physiologische Triebkraft " of the Germans. 



322 



(EDEMA AND NEPHRITIS 



disappear. The " secretory " activities of absorbing (and 
secreting) membranes as evidenced through their " selective " 
absorption and secretion of water and dissolved substances we 
have already discussed in the preceding paragraphs. Their 
"physiological " activity retains a meaning only in the sense 
that the absorbing (and secreting) membranes of multicellular 
organisms contain living cells in each of which there are occur- 
ring well-ordered series of chemical and physico-chemical reac- 
tions which are capable of influencing the colloid constitution 
of these membranes. To do this is to influence the nature 
of the phases and the conditions of equilibrium in our ab- 
sorptive (secretory) systems, and therefore secretion and absorp- 
tion. But these reactions are not impossible to analyze. 

The need for the " physiological driving force " also disappears. 
Such was originally called upon to help explain such a fact as the 
absorption of a solution, from the intestine for example, when the 
pressure under which it stands in the lumen of the gut is less 
than that of the pressure of the blood in the mesenteric veins 
through which it is being absorbed (E. Waymouth Reid). Such 
a view regards absorption as a process in which water is forced 
into the tissues. This is not what happens. It is sucked in, 
and such a process can occur even when the hydrostatic pressure 
in the veins happens to be a few millimeters above that in the 
lumen of the intestine. The pressures produced in the swelling 
of hydrophilic colloids are enormous as compared with the highest 
hydrostatic (arterial blood) pressures ever observed in animals 
possessed of a circulation. The use of " physiological" poisons 
to illuminate the " physiological" element in absorption (or 
secretion) proves nothing. Such poisons simply constitute a 
direct or indirect means of altering the physico-chemical state of 
the absorbing (or secreting) structures. And is it not the problem 
of physiology to state in terms of physics and chemistry just 
what this " normal " absorption (and secretion) is? When we 
use a " physiological " poison we have to explain the action of 
the poison along with what constitutes " normal " absorption 
(and secretion). 

Nothing has perhaps so effectively hampered the acceptance 
of the belief that absorption (and secretion) would ultimately 
prove themselves completely analyzable physico-chemically, 
and fostered the continuation of the " physiological," " secretory/' 



ABSORPTION, SECRETION — COMPLEX ORGANISM 323 



etc., notions of absorption (and secretion) as a series of experi- 
ments first described by R. Heidenhain, and more recently 
repeated in modified form by E. Waymouth Reid and Otto 
Cohnheim. The most striking of these is the often quoted 
experimental finding that a dog will absorb his own blood serum. 
A word regarding experiments of this character may serve 
to show how they are interpretable on the basis of the colloid 
theory of water secretion and absorption. In not one of these 
experiments, except where the possibility of the presence of pro- 
teolytic ferments is not excluded, is the serum or plasma completely 
absorbed. The reason why some is absorbed, but never all, is 
clear from the following: 

Blood serum and blood plasma are not blood; they are blood 
minus much of its hydrophilic colloid content. They are not 
solutions in which all the water is bound to colloid material 
as in normal blood, but they contain " free " water over and 
above that necessary to saturate the colloids remaining in the 
" serum " or the " plasma." When they are introduced into 
the intestine they are therefore absorbable but only in so far 
as they contain free water (and a certain proportion of salts, 
urea, etc.) The absorption comes to a halt as soon as water 
has been absorbed down to the point where the remaining water 
is combined with colloid. In these experiments things are there- 
fore not the same on both sides of the absorbing membrane. 
The animal does not absorb serum or plasma as such, much less 
what these authors seem at times to try to have us believe, namely, 
something identical with blood itself. The animal absorbs some 
water and a few dissolved substances, and it does this for the 
same reason that it absorbs under similar circumstances any 
ordinary " physiological " salt solution. 

• § 4 

Of the different factors that are cataloged in our treatises 
on physiology, and which have at various times and in various 
ways been looked upon as active in this problem of absorption, 
only one remains to be discussed — that of imbibition. What 
Adolph Fick 1 has called molecular imbibition is but another 

1 Adolph Fick: Medizinische Physik, 3d Ed., Braunschweig (1885). 



324 OEDEMA AND NEPHRITIS 

term for what we to-day call the absorption of water by hydrophilic 
colloids. It is, therefore, of interest that mention is made 
of imbibition as being important in the general problem of absorp- 
tion as far back as 1881. 1 But the real significance of imbibition 
as a factor concerned in absorption was only pointed out more 
recently by H. J. Hamburger. 2 This author correctly empha- 
sized the theoretical importance of his observation that animals 
absorb various solutions from their peritoneal (and other serous) 
cavities after death. While we cannot agree with the details 
of his ideas outlining the way in which the forces of imbibition 
act normally, a discussion into which it is not necessary to go 
here, there is no disputing his claim that imbibition plays a role. 
But Hamburger does not regard imbibition as the most sig- 
nificant factor in absorption, and continues to hold to the ideas 
of filtration, osmotic pressure and the " mitschleppende Wirkung " 
of the circulation as also concerned in the process. Nor does 
he suggest any way by which a fluid absorbed by imbibition is 
again gotten rid of. In view of all this, it seems to me that we 
owe a special debt to Franz Hofmeister, 3 who, as early as 
1891, pointed out that the salts which make (partially) water- 
soaked gelatin discs give off their water (secrete it) are identical 
with the so-called saline cathartics, and suggested that the two 
processes are in essence the same. In spite of the numerous 
papers on alimentary absorption and secretion, and on the mode 
of action of the saline cathartics that have appeared since Hof- 
meister' s writings, there seems little question that we are destined 
to return to Hofmeister's conclusions, and find in them not only 
an explanation of the mode of action of these cathartic salts, but 
a model of that which constitutes the essence of absorption and 
secretion. 

l W. von Wittich: Hermann's Handbuch d. Physiol., 5, 2ter Theil, 
Leipzig (1881). 

2 H. J. Hamburger: Osmotischer Druck und Ionenlehre, 2, 108 and 164, 
Wiesbaden (1904). 

3 Franz Hofmeister: Arch. f. exp. Path. u. Pbarm., 28, 210 (1891). 



ABSORPTION, SECRETION — COMPLEX ORGANISM 325 



III 

ON SECRETION 
1. Introduction 

The paragraphs on absorption have shown how water and 
various dissolved substances get from the lumen of the gut (or 
any other point of absorption, as the skin, peritoneum or other 
serous cavity) into the absorbing colloid mucous membrane 
and through this into the blood and lymph. The blood and 
lymph are ultimately united when they empty into the large 
veins near the heart. What is the fate of the absorbed water 
and the dissolved substances? Clearly, two possibilities present 
themselves: they may be retained in the various cells, tissues 
and organs of the body, or they may again be given off (perhaps 
after having suffered antecedent chemical changes) through the 
various secretions from the body. Under the first of these 
headings the body cells come to absorb from the blood the amount 
of water requisite to maintain their normal water content (normal 
turgor) ; or, if for any reason the hydration capacity of the hydro- 
philic colloids in any cell, tissue or organ, or in the organ- 
ism as a whole has been abnormally heightened, then these 
absorb more than the usual amount of the proffered water, and 
swelling to more than normal size give evidence of an oedema in 
the involved parts. The dissolved substances brought with the 
water are accepted or rejected by the body cells depending upon 
whether their content of these is or is not in equilibrium with 
the concentration of these same substances in the blood. Oxy- 
gen, food-stuffs, substances like the salts when present beyond 
their " physiological " concentrations, various poisons or medici- 
nal agents which by accident or design have gotten into the 
blood are thus taken up, while carbonic acid and the products of 
cell metabolism are for the same reason given off. 

What water remains above the amount necessary to satisfy 
the hydration capacity of the body colloids as well as the dis- 
solved substances representing, for example, the products of 
cell activity, are lost through the secretions. Why this happens 
and how is our next problem. As the kidney represents both 
from a qualitative and a quantitative point of view the great 



326 



(EDEMA AND NEPHRITIS 



secretory organ of our bodies, we will limit our discussion largely 
to it. Our remarks upon it may with little modification be applied 
to any of the other secreting organs, as the skin, the salivary 
glands, the stomach, etc. The following paragraphs do not 
presume to give a complete analysis of the physiology and path- 
ology of kidney function; they try, however, to show how the 
general problem can be broken up into a series of smaller ones. 
An attempt is made to explain some of these, while others are 
correlated with problems which still await an answer in physical 
chemistry. 

2. General Remarks on the Structure of a Secreting System in 
the Complex Organism 

The kidney function shows in common with all secretory 
systems (1) a secretion obtained through (2) a secreting mem- 
brane from (3) a source of some kind. In the case of the kidney 
these terms are synonymous with urine, kidney parenchyma 
and blood. In their physico-chemical properties they parallel 
the three phases discussed above as entering into the construction 
of any absorbing system. 1 

(1) The urine is essentially a watery solution of various electro- 
lytes and non-electrotytes. At times it may be acid, at other 
times neutral or even alkaline in reaction. Under normal cir- 
cumstances, as it escapes from the uriniferous tubules, it contains 
so little colloid material that for our purposes it is negligible. 
Albumin, mucin, etc.,' are, of course, present even in normal 
urine, though in such small amounts that they escape notice 
when only our ordinary analytical methods are employed. 

(2) The secreting membrane through which the urine comes is 
made up of all the cellular and intercellular elements found 
between the urine on the one hand and the circulating blood 
on the other. It is, in other words, the kidney itself. From a 
histological standpoint this membrane differs somewhat in its 
different parts. To start with, the membrane consists of a layer 
of endothelial cells (of the blood capillaries) covered by a layer 
of the cells of Bowman's capsule, the whole joined together by a 
certain amount of intercellular substance. While the endothelial 
cells continue throughout the length of the membrane the addi- 
tional covering changes, first to the cells of the convoluted tubules, 



ABSORPTION, SECRETION— COMPLEX ORGANISM 327 



then to those of the different parts of the loop of Henle, then 
to those of the second set of convoluted tubules and finally to 
the cells of the collecting tubules. The membrane, from a 
physico-chemical point of view, is colloid in constitution and simi- 
lar in its general properties to the more solid protein colloids 
such as fibrin or gelatin. But in no sense are the different por- 
tions of the tube made up of exactly the same colloid material, 
either in a chemical or a physical sense, as clearly indicated by 
the fact that dyes, for example, do not stain all portions equally. 

The membrane, moreover, is alive. As we said in discussing 
absorption, this means that a series of more or less independent 
chemical and physico-chemical reactions are thereby introduced 
into our general problem of secretion which demand additional 
care in the analysis of the whole problem. 

(3) The physico-chemical properties of the blood have been 
previously described. It represents a liquid colloid menstruum 
in which float the more solid colloid corpuscles, the whole showing 
the general physico-chemical reactions characteristic of simple 
proteins. 

3. A Model Illustrating Some Phases of Urinary Secretion 

Before continuing our main argument it is well to digress here 
and describe a somewhat crude but quite efficient model of urinary 
secretion (Fig. 107). Familiarity with it may help to a better 
understanding of what follows. This model consists of a layer 
of finely powdered (preferably faintly acid) blood fibrin (b) in 
the bottom of an ordinary calcium chlorid tube (C), the outlet of 
which has been plugged with a little cotton (a) to keep the fibrin 
from falling through. The overflow tube (c) keeps the liquid in 
C at a constant level. The whole is fastened in an upright 
position into a support. Above it are clamped two large separ- 
ator funnels (A and B) furnished with stopcocks which permit 
regulation of outflow. 

If now a " physiological " salt solution contained in one of 
the funnels (m/8 or 0.72% NaCl) is allowed to flow into the cal- 
cium chlorid tube in such a way that a constant level is main- 
tained, it is seen to pass through the fibrin (which swells some- 
what) and to escape in drops at the lower end of the tube. The 
rate at which the salt solution escapes (cc. in units of time) 



328 



(EDEMA AND NEPHRITIS 



remains constant for indefinite periods of time if the pressure 
remains the same. If the level of the solution in' the calcium 

chlorid tube is raised, 
then the " secretion " 
occurs more rapidly. 

When a dilute acid 
or a sodium chlorid 
solution containing an 
acid is substituted for 
the pure sodium chlorid 
solution, the rate of out- 
flow is seen to diminish 
gradually, and finally, 
perhaps, to stop entirely. 
At the same time the 
fibrin swells and the 
solution that drips 
through gives an albu- 
min ring with nitric 
acid. If the pure sodium 
chlorid solution is re- 
turned to, or enough of 
this salt, or better, sodi- 
um citrate, tartrate or 
sulphate (or any other 
of the " saline diuretics ") 
is added to the acid 
solution, the secretion 
can be made to recom- 
mence, first slowly, then 
more rapidly, and ulti- 
mately the normal, or 
even a better flow may 
be obtained. At the 
same time the albumin 
ring disappears from 
the liquid that passes 
through. 

If various non-elec- 
trolytes (ethyl or methyl 




Figure 107. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 329 



alcohol, or urea are used in place of the salt solutions, either 
alone or in combination with an acid, the changes in rate of out- 
flow are scarcely noted, if at all. 

The interpretation of these simple facts offers no particular 
difficulties. The liquids introduced into the calcium chlorid 
tube escape below after traversing a capillary bed formed by a 
hydrophilic colloid. Acids of various kinds which make the 
fibrin swell, decrease the rate of outflow by decreasing the size 
of the capillaries. The effect of neutral salts and acids on the 
swelling of fibrin explains why such salts as the citrate, sulphate 
and tartrate of sodium can make a layer of fibrin permeable 
to water once more, after it has been rendered impermeable 
by a pure acid. Albumin appears in the filtrate when it does 
because the fibrin is (pseudo-) soluble in acid solutions. It 
becomes less in amount or disappears entirely when enough of 
different salts is added, because these reduce the " solubility " 
in acids. 

The question now arises whether this model of secretion has 
anything in common with the physiological and the pathological 
secretion of urine. I believe it has, though not in as coarse 
a form as the rough analogy between the model and certain 
phases of urinary secretion might at first suggest. The model 
here described was, as a matter of fact, constructed to give 
tangible evidence to conceptions of urinary secretion which 
familiarity with the well-known facts of kidney physiology 
and my own experiments had led me to formulate in my mind. 
Just how far I think the model simulates conditions observed 
in experiments on the kidneys will appear later. 

We will take up now a series of experimental findings on the 
secretion of urine which it seems to me can be interpreted, in the 
light of our knowledge regarding colloids, in a different and 
simpler way than is generally done. Our discussion will deal 
separately with the subjects of the secretion of water by the 
kidneys, and the secretion of substances dissolved in the water. 
Here too, many writers in physiology and pathology to this 
day look upon the two as parallel processes. As a matter of 
fact, they constitute separate problems, and should be dealt 
with separately. 



330 



(EDEMA AXD NEPHRITIS 



4. The Output of Water by the Kidney 

We are not surprised to find that the secretion of urine ceases 
(practically) during absolute starvation. If the colloids of the 
body as a whole are holding on to all the available water, if, in 
other words, an amount more than necessary to saturate them 
is not present, then none is left over to be secreted. Only as 
the tissues undergo gradual consumption during the process 
of starvation or their colloids suffer changes which decrease 
their capacity for holding water is any liberated. On the other 
hand, if a non-thirsting organism (as I will, for short, call one 
whose colloids are saturated with water) consumes a quantity 
of water, an amount of urine is excreted (skin and lung ignored), 
after a variable length of time, which is equivalent to the amount 
of water that was drunk. (Not to do so means the development 
of an oedema.) It does not matter how this water was con- 
sumed. It may simply have been swallowed or have been 
experimentally introduced into the gastro-intestinal tract, or 
it may have been injected into the peritoneal cavity, under 
the skin, or directly into the blood. By a process of colloid 
absorption we ultimately reduce all these to one, namely to 
the presence of water in the blood. What becomes of the water 
after it has gotten into the blood, as into the venous blood 
returning from the alimentary tract, is our next problem. 

In its transit through the lungs the venous blood coming from 
the alimentary tract loses the carbonic acid responsible for the 
increased hydration capacity of its colloids. As soon as this 
has happened the blood contains more water than the blood 
colloids are capable of holding, and so this separates off as urine 
or as some other secretion. 1 

In order to obtain a secretion from the kidney (or any other 
gland) conditions the reverse of those which favor absorption must be 
established. Thus, highly venous blood favors absorption, but 
secretion can occur only when a gland is supplied with arterialized 
blood (blood low in carbonic and other acids and high in oxygen). 
Let us now consider some experiments which prove the truth 
of these contentions. 

1 1 have often been asked why the secretion does not occur into the lungs 
(where the carbonic acid escapes). The truth is that just as much water 
is lost daily (by evaporation) through the lungs as through the kidneys. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 331 

Since the presence of free water in the blood is in my opinion 
the sine qua non for urinary secretion, let us first see what is the 
effect on secretion of introducing a certain amount of this into 
the circulation. Since distilled water is destructive to the red 
blood corpuscles we will inject instead a salt solution. To 
accomplish such injection without injury to the animal we make 
use of the apparatus shown in Fig. 108. The graduated cylin- 
der c is closed with a soft rubber stopper provided with two glass 
. tubes bent as shown in the diagram and supplied with the 
rubber tubes a and b ending 
respectively in the injection 
needle n and the pressure bulb 
d. When d is compressed, any 
fluid contained in c is forced 
into the delivery tube. After 
the air is driven out of this the 
needle n is inserted into the 
ear vein of a rabbit and held 
in place by two small artery 
clamps. By pressure upon d 
the fluid may now be injected 
directly into the animal's cir- 
culation at any ■ rate desired. 
The animal is comfortably tied 
into an animal holder and the 
urine is collected through a 
small soft rubber catheter in- 
serted into the bladder. Un- 
less poisonous substances are Figure 108. 
injected, the whole procedure 

does not injure an animal in the slightest, so that it may (with 
suitable periods of rest between) be used over and over again. 
No operations are necessary, the animal suffers no pain and 
therefore there is no need for anesthetics. These prolific sources 
of error are hence eliminated. 

In Fig. 109 are shown the effects on urinary output in a rabbit 
of injecting intravenously the same amount (125.9 cc.) of dif- 
ferently concentrated sodium chlorid solutions. 1 All the curves 

1 James J. Hogan and Martin H. Fischer: Kolloidchem. Beihefte, 3, 
304 (1912). 




in this figure were obtained 
from the same animal. The 
lowermost curve a serves 
as a control and indicates 
normal urinary secretion. 
The curves are constructed 
by plotting time on the 
horizontal and the amount 
of urine secreted in fifteen 
minute intervals on the 
vertical. 

Curve b shows the effect 
of injecting at the uniform 
rate of 10 cc. every five 
minutes m/8 (0.729 per 
cent) sodium chlorid. As 
is clearly evident such in- 
jection soon increases the 
amount of urine secreted. 

Curve c shows the effect 
of injecting an equivalent 
amount of a sodium chlorid 
solution alleged to be more 
nearly "isosmotic" or " iso- 
tonic" with the tissue fluids 
of a rabbit, namely a 0.92 
per cent solution. As is 
readily apparent, in spite 
of the fact that exactly the 
same amount of water was 
injected and at exactly the 
same rate the urinary out- 
put is still further increased. 
We also notice that the 
effect of this injection evi- 
dences itself sooner upon 
the secretion. 

Curves d and e show 
the effects of injecting 
m/4 (1.459 per cent) and 



ABSORPTION, SECRETION— COMPLEX ORGANISM 333 



m/2 (2.909 per cent) sodium chlorid solution. Again, in 
spite of the fact that the same amount of water has been in- 
jected and at the same rate, the loss of water from the body 
occurs the more rapidly and is the greater the higher the con- 
centration of the injected salt. In these later experiments little 
or none of the injected water is retained in the body and if enough 
salt is injected with the water, the animal loses more water than 
was injected. 1 

How are we to interpret these simple facts? As previously 
emphasized, the whole animal, including his blood and lymph, 
represents a system of hydrophilic colloids which are saturated 
with water. This colloid system cannot take up any more water 
or give off any except as it first suffers chemical or physico-chem- 
ical changes which either increase or decrease the capacity of 
these colloids for holding water. If the system composing the 
body is saturated with water then it cannot, of course, take up 
any more, and so if " free " water in the form of a " phy- 
siological " (m/8 or 0.729 per cent) salt solution is injected, this 
cannot be retained, but must escape as urine (or some other 
secretion) . 

But why does a stronger salt solution bring about an earlier 
increase in urinary output and a greater one? It is ordinarily 
said that this occurs because the salt " stimulates " the kidney 
in some mysterious way. The explanation is really simpler. 
The salts decrease the capacity of the body colloids (protein 
colloids) for water, and this the more the higher the concentra- 
tion of the salt. The higher, therefore, the concentration of 
salt in our injection mixture the higher must it be in the blood, 
and in consequence (after diffusion) in all the tissues of the body. 
By injecting a strong salt solution we therefore not only inject 
a certain amount of free water as before, but we make the tissues 
give off water. This " free " water is then added to that which 
we injected and it is the sum of the two which appears as 
urine. The administration of salt increases the water output through 
the kidney primarily, not because of any effect upon the kidney 
but because of an effect upon the body as a whole. Incidentally, 
we observe that contrary to much clinical teaching, sodium chlorid 

1 These facts are confirmed by the experiments of H. Roger and 
Garnier: Arch, de Med. exp., Mai (1913); La Presse Medicale, 885 (1913) 
who, however, make no attempt to interpret their findings. 



334 



(EDEMA AND NEPHRITIS 



administration does not lead to a retention of water in the body and 
thus to an oedema, but just the reverse. This is in harmony with 
our previous observations on simple colloids. 

Curves a, b, c, d and e of Fig. 91 have been constructed from 
the observations contained in Experiments 12, 13, 14, 15 and 16. 



Experiment 12. Normal Urinary Secretion. — Belgian male rabbit. 
Weight 2495 grams. Fed on mixed standard diet. Tied into animal 
holder and catheterized. No anesthesia. 



Time. 


Urine 


in cc. 


Remarks. 


11.15 






Tied down, catheterized. 


11.30 








11.45 


1 


6 


Clear, yellow, alkaline, no albumin. 


12.00 


6 


4 


Same. 


12.15 


4 


8 


Same. 


12.30 





9 


Same. 


12.45 


1 


7 


Same. 


1.00 


1 


3 


Same. 



Animal released in good condition. 

Total urine in the period of orfe and three-quarter hours, 16.7 cc. 



Experiment 13. Injection Fluid: m/8 (0.72 per cent) NaCl. — 
Belgian male rabbit. Weight 2495 grams. Kept on standard mixed diet 
of clover hay, oats, corn and greens. 

124.9 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. It was estimated that this amount 
was equivalent to the total volume of blood of the animal. No 
anesthetic. 



Time. 


Urine in cc. 


Remarks. 


2.15 


21.5 


Tied down, catheterized, injection begun. Urine, clear 






yellow, neutral, no albumin. 


2.30 


0.3 


Same. 


2.45 


1.0 


Clear, yellow, faintly alkaline, no albumin. 


3.00 


1.9 


Same. 


3.15 


7.7 


Same. 






Injection stopped. 


3.30 


14.0 


Clear as water, faintly alkaline, no albumin. 


3.45 


14.0 


Same. 


4.00 


14.0 


Same. 


4.15 


16.0 


Same. 


4.30 


11.2 


Same. 


4.45 


4.8 


Same. 



Animal released in good condition. 

Total urine in two and one-half hour-period since beginning of injec- 
tion: 84.9 cc. 

Urine secreted in the first two hours: 68.9 cc. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 335 



Experiment 14. — Injection Fluid: 0.92 per cent NaCl. — Belgian male 
rabbit. Weight, 2495 grams. Kept on standard mixed diet. 124.9 cc. of 
the above solution are injected into ear vein at uniform rate of 10 cc. 
every 5 minutes. This amount was estimated as equivalent to the total 
volume of blood of the animal. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


9 


30 


2 


5 


Tied down, catheterized, injection begun. Urine clear, 
yellow, no albumin. 


9 


45 


7 


5 


Clear, yellow, alkaline, on albumin. 


10 


00 


24 





Clear as water, yellow, faintly alkaline, no albumin. 


10 


15 


22 





Same. 


10 


30 


21 





Clear as water, neutral, no albumin. 
Injection ended. 


10 


45 


5 





Clear as water, yellow, faintly alkaline, no albumin. 


11 


00 


5 


2 - 


Cloudy, pale yellow, faintly alkaline, no albumin. 


11 


15 


11 


1 


Same. 


11 


30 


9 


5 


Yellow, alkaline, no albumin. 


11 


45 


8 


5 


Same. 


12 


00 


8 


2 


Same. 



Animal released in good condition. 

Total urine in two and one-half hour-period since beginning of injec- 
tion; 123.3 cc. 

Urine secreted in the first two hours: 105.3 cc. 



Experiment 15. Injection Fluid: m/4 (1.45 per cent) NaCl. — Belgian 
male rabbit. Weight 2495 grams. Kept on standard mixed diet. 
124.9 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. This amount was estimated as equiv- 
alent to the total volume of blood of the animal. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


9.45 




Tied down, catheterized, injection begun. 




3.0 


Cloudy, yellow, alkaline, no albumin. 


10.00 


19.5 


. Clearing, alkaline, no albumin. 


10.15 


36.0 


Clear as water, faintly alkaline, no albumin. 


10.30 


41.0 


Same. 


10.45 


34.5 


Same. 






Injection ended. 


11.00 


18.5 


Same. 


11.15 


8.5 


Same. 



Animal released in good condition. Drinks water at once. 
Total urine in the one and one-half-hour period since beginning of 
injection: 159.0 cc. 

Experiment 16. Injection Fluid: m/2 (2.8 per cent) NaCl. — Belgian 
male rabbit. Weigh 2495 grams. Kept on standard mixed diet. 
124.9 cc. of the above solution are injected into ear vein at uniform 



336 (EDEMA AND NEPHRITIS 



rate of 10 cc. every five minutes. This amount was estimated as 
equivalent to the total volume of blood of the animal. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


1U(. to 




Tied down, catheterized, injection begun. 




4.0 


Cloudy, yellow, alkaline, no albumin. 


11.00 


64.0 


Clearing, alkaline, no albumin. 


11.15 


84.0 


Clear as water, neutral, no albumin. 


11.30 


48.0 


Same. 


11.45 


28.0 


Same. 






Injection ended. 


12.00 


33.0 


Same. 


12.15 


3.5 


Same. 


12.30 


22.0 


Same. 


12.45 


6.0 


Same. 



Animal released in good condition. Drinks water at once. 

Total urine in two-hour period since beginning of injection: 288.5 cc. 

The correctness of these views can at once be tested by sub- 
stituting for the simple salt solutions used above, one in which 
the water is not " free," but united to a colloid. The natural 
liquid which has these properties is, if our reasoning is correct, 
blood itself. We should therefore expect that the injection of 
no amount of blood would yield any increased flow of urine. 
That it does not is a familiar fact since the experiments of E. 
Ponfick 1 and R. Magnus, 2 only its interpretation has until 

now been missing. Curves 
a, b, c and d of Fig. 110 and 
the Experiments 17, 18, 19 
and 20, from which they 
were constructed, show that 
the injection of a solution in 
which all the water is united 
■ Figure 110. to a colloid leads to no in- 

crease in urinary output. In 
these experiments we did not inject whole blood, but blood 
serum from freshly drawn horse blood obtained under aseptic 
conditions and permitted to coagulate in an ice box. 

Experiment 17. Injection Fluid: The Serum of Horse Blood. — 
White Belgian rabbit. Weight 1692 grams. Kept on standard mixed 
diet. 

42.4 cc. of the serum are injected into ear vein at uniform rate of 

iE. Ponfick: Virchow's Arch., 62, 277 (1875). 

2 R. Magnus: Arch. f. exp. Path. u. Pharm., 45, 210 (1901). 




ABSORPTION, SECRETION— COMPLEX ORGANISM 337 



10 cc. every 5 minutes. This amount was estimated as equivalent to 
one-half the total volume of blood of the animal. No anesthetic. 



Time 


Urine in cc. 


T? ATYI O tItQ 
J. VCHlal KC'o 


10.45 




Tied down t cftttictGrizccii injection begun 




4.0 


Thick yollow sJk&linc, no filfoumin 


11 00 


1 2 


A 1 L- q 1 i r> a Tt d q 1 }-» n rn i n 


11 07 3^ 




Tn ipf>f inn An rl prl 


11 15 


3 




11^30 


9^0 


Clear, alkaline, traces of albumin. 


11.45 


3.0 


Alkaline, albumin, no casts. 


12.00 


0.8 


Same. 


12.15 


0.6 


Alkaline, less albumin, no casts. 


12.30 


1.2 


Same. 


12.45 


0.7 


Alkaline, faint trace of albumin, no casta. 


1.00 


0.4 


Strongly alkaline, trace of albumin. 


1.15 


0.8 


Same. 


1.30 


0.7 


Same. 


1.45 


0.5 


Same. 


2.15 


0.5 


Same. 


2.45 


0.6 


Same. 



Animal released in good condition. 

Total urine in four-hour period since beginning of injection: 23.0 cc. 
Urine secreted in first two hours: 19.9 cc. 



Experiment 18. Injection Fluid: The Serum of Horse Blood. — 
White and Belgian male rabbit. Weight 1585 grams. Kept on standard 
mixed diet. 

79.1 cc. of the serum are injected into ear vein at uniform rate of 
10 cc. every five minutes. This amount was estimated as equivalent 
to the total volume of blood of the animal. No anesthetic. 



Time. 


Urine 


in cc. 


Remarks. 


11.25 






Tied down, catheterized, injection begun. 




2 


5 


Yellow, alkaline, no albumin. 


11.40 


1 





Same. 


11.55 


0.6 


Cloudy, alkaline, no albumin. 


12.02 






Injection ended. ( 


12.10 


1 


3 


Cloudy, alkaline, trace of albumin. 


12.25 


5 


5 


Cloudy, faintly alkaline, albumin, no casts. 


12.40 


3 


5 


Same. 


12.55 


3 


5 


Slightly cloudy, alkaline, albumin. 


1.10 


3 


5 


Alkaline, trace of albumin. 


1.25 


3 


5 


Same. 


1.55 


3 


5 


Cloudy, alkaline, red blood corpuscles, no casts. (Presence 
of blood due to traumatic bleeding in the bladder?). 


2.25 


4 


2 


Trace of albumin, red blood corpuscles, no casts. 


2.55 





6 


Bloody, alkaline, albumin, red blood corpuscles, no casts. 



Animal released in good condition. 

Total urine in the three and one-half hour period since beginning of 
injection: 31.1 cc. 

Urine secreted in the first two hours: 22.8 cc. 



338 



(EDEMA AND NEPHRITIS 



Experiment 19. Injection Fluid: The Serum of Horse Blood. — 
Himalaya rabbit. Weight 1564 grams. Kept on standard mixed 
diet. 117.3 cc. of the serum are injected into the ear vein at uniform 
rate of 10 cc. every five minutes. This amount was estimated as equiv- 
alent to one and one-half times the total volume of blood of the animal. 
No anesthetic. 



Time. 


Urine 


in cc. 


Remarks. 


3.30 






Tied down, catheterized, injection begun. 




1. 





Thick, yellow alkaline, no albumin. 


3.45 


0. 


3 


Same. 


4.00 


2 


6 


Thick, yellow, strongly alkaline, trace of albumin. 


4.15 


2. 


6 


Thick, yellow, strongly alkaline, albumin. 


4.30 


3. 





Alkaline, albumin. 








Injection ended. 


4.45 


4. 


7 


Alkaline, more albumin, some traumatic blood. 


5.15 


4. 


2 


Alkaline, more albumin, red blood corpuscles. 


5.30 


0. 


3 


Albumin. 


5.45 


0. 


2 


Albumin. 



Animal released in good condition. 

Total urine in the two hour period after beginning of injection: 
17.7 cc. 



Experiment 20. Injection Fluid: The Serum of Horse Blood. — 
White male rabbit. Weight 1371 grains. Kept on standard mixed diet. 
110 cc. of the serum are injected into ear vein at uniform rate of 10 cc. 
every five minutes. This amount was estimated as equivalent to 
one and two thirds times the total volume of blood of the animal. No 
anesthetic. 



Time. 


Urine 


in cc. 


Remarks. 


4.45 






Tied down, catheterized, injection begun. 


5.00 


4 


2 


Clear, yellow, acid, no albumin. 


5.15 





5 


Clear, no albumin. 


5.30 





4 


Clear, faint trace of albumin. 








Injection ended, animal in good condition. 


5.45 





4 


Clear, trace of albumin. 


6.00 





3 


Thick, bloody, more albumin. 


6.02 






The animal dies. 



Total urine since beginning of injection: 2.4 cc. 
Autopsy: The heart and blood vessels- are filled with blood. The 
peritoneal and pleural cavities are empty. 



As we proceed we shall find further experimental evidence 
for the truth of these views. The injected blood serum remains 
in the blood vessels. To the important physiological and thera- 
peutic consequences of this we shall also return later. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 339 



5. On the Colloid-chemical Action of the Diuretic Salts. 1 
the Saline Diuretics Produce Diuresis 



How 



Under ordinary circumstances the water output from the 
kidneys occurs so uninterruptedly and within such " normal " 
limits that we take it for granted. But 
in physiology, in pharmacology and 
particularly in the practical medicine 
of every day, when for any reason we 
observe a diminution in urinary out- 
put, then a discussion of " diuretics " 
develops, and of the means of increas- 
ing the observed urinary output. In 
the end certain " saline diuretics " 
may be prescribed which we know 
from both physiological and clinical 
experience to be capable of increasing 
the urinary output. How such diu- 
retics act has been much debated. 
As the following shows, the saline diu- 
retics are nothing but those salts which 
without being markedly poisonous are 
the most powerful dehydrants of the 
body colloids. They owe their action 
primarily not to any effect upon the 
kidney, but to an effect upon the body 
as a whole. By diffusing into the tissues 
of the body they liberate water from 
them, and their diuretic activity is but 
an expression of the amount of water 
they are thus able to liberate. 

The proof for this is easily brought. 
We need but make use of the pro- 
cedure previously employed and inject 
intravenously into animals equimolar 
amounts of different salts. When 
definite volumes (175 cc.) of equimolar 

solutions are thus injected at a uniform rate into rabbits they 

1 Martin H. Fischer and Anne Sykes: Science, 37, 845 (1913); Kolloid- 
Zeitschr., 13, 112 (1913). 




Figure 111. 



340 



(EDEMA AND NEPHRITIS 



lead to an increased output of urine which parallels the order in 
which they dehydrate protein colloids. 

For purposes of control Curve x of Fig. Ill and Experiment 21 
are introduced. This shows the normal urinary output in a 
rabbit kept on our standard laboratory diet of hay, oats, corn 
and greens when simply tied comfortably into an animal holder 
and catheterized. 

The remaining curves with their corresponding experiments 
need no further explanation, for the experimental conditions 
were the same in all cases. The difference lies in the various 
salts injected. We adopted the effects of injection of m/4 
sodium chlorid solution as a standard for comparison. Curve a 
of Fig. Ill shows the urinary output of a rabbit when injected 
intravenously with such a solution. If a part of the sodium 
chlorid is replaced by an equimolar amount of magnesium 
chlorid, strontium chlorid or calcium chlorid, the urinary out- 
put is markedly increased. In place of the 147.4 cc. of urine 
secreted in the control experiment with sodium chlorid, we 
now obtained 179.3 cc, 185.5 cc. and 224.2 cc, respectively. 
The bivalent metals act as more powerful diuretics than the 
monovalent, and the order in which they produce diuresis is the 
same as the order in which they dehydrate simple (protein) col- 
loids in test-tube experiments. This is shown by the curves of 
Fig. Ill as well as Experiments 22, 23, 24 and 25, from which 
they are constructed. 



Experiment 21. Normal Urinary Secretion. — White male rabbit 
F. Weight 2639 grams. Kept on standard mixed diet. Tied into 
animal holder and catheterized. No anesthetic. 



Time. 


Urine 


in cc. 


Remarks. 


10.30 





6 


Tied down, catheterized. 

Thick, yellow, alkaline, no albumin, no sugar, no casts. 


10.45 





8 


Same. 


11.00 





2 


Same. 


11.15 








11.30 


3 





Same. 


11.45 


1 


5 


Same. 


12.00 


2 





Same. 


12.15 


1 


5 


Same. 


12.30 


2 





Same. 



Animal released in good condition. 
Total urine in two-hour period, 10.0 cc. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 341 



Experiment 22. Injection Fluid: m/4 NaCl— White male rabbit 
B. Weight 2129 grams. Kept on standard mixed diet. 175 cc. of 
the above solution are injected into ear vein at uniform rate of 10 cc. 
every five minutes. No anesthetic. 



Time. 


Urine in cp. 


Remarks. 


10.30 




Tied down, catheterized, injection begun. 




10.0 


Alkaline, no albumin, no casts. 


10.45 


0.4 


Same. 


11.00 


9.0 


Same. 


11.15 


11.0 


Same. 


11.30 


19.5 


Same. 


11.45 


32.0 


Clear as water, alkaline, no albumin, no casts. 


11.57^ 




Injection ended. 


12.00 


41.0 


Same. 


12.15 


22.5 


Same. 


12.30 


12.0 


Same. 



Animal released in good condition. 

Total urine in two-hour period since beginning of injection, 147.4 cc. 



Experiment 23. Injection Fluid: 180 cc. m/4 NaCl+20 cc. m/4 
MgCl 2 . — White male rabbit B. Weight 2146 grams. Kept on standard 
mixed diet. 175 cc. of the above solution are injected into ear vein 
at uniform rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine 


in cc. 


Remarks. 


11. 15 




Tied down, catheterized, injection begun. 
Yellow, faintly alkaline, no albumin, no casts. 





5 


11.30 


2 





Clearing, alkaline, no albumin, no casts. 


11.45 


13 


5 


Slightly cloudy, no casts. 


12.00 


19 


5 


Same. 


12.15 


36 


5 


Same. 


12.30 


36 


5 


Slightly cloudy, alkaline, sugar present, no casts. 


12.45 


34 





Clear, neutral, no albumin, sugar present, no casts. 


1.00 


19 





Same. 


1.15 


18 


3 


Same. 



Animal released in good condition. 

Total urine in two-hour period since beginning of injection, 179.3 cc. 

Experiment 24. Injection Fluid: 180 cc. m/4 NaCl+20 cc. 
m/4 SrCl 2 — White male rabbit B. Weight 2170 grams. Kept on 
standard mixed diet. 175 cc. of the above solution are injected 
into ear vein at uniform rate of 10 cc. every five minutes. No 
anesthetic. 



342 



(EDEMA AND NEPHRITIS 



Time. 


Urine 


in cc. 


Remarks. 


2.45 






Tied down, catheterized, injection begun. 




5 





Yellow, faintly alkaline, no albumin, no sugar, no casts. 


3.00 


2 


2 


Same. 


3.15 


25 





Same. 


3.30 


33 


o 


Slightly cloudy, faintly alkaline, no albumin, sugar pres- 








ent, no casts. 


3.45 


34 


5 


Same. 


4.00 


31 


5 


Same. 


4. 12 J* 






Injection ended. 


4.15 


37 





Same. 


4.30 


14 





Same. 


4.45 


8 


4 


Same. 



Animal released in good condition. 

Total urine in two-hour period since beginning of injection: 185.5 cc. 



Experiment 25. Injection Fluid: 180 cc. m/4 NaCl+20 cc. 
m/4 'CaCl 2 . — White male rabbit J. Weight 2214 grams. Kept on 
standard mixed diet. 175 cc. of the above solution are injected into ear 
vein at uniform rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


3.15 




Tied down, catheterized, injection begun. 




33.0 


Thick, cloudy, alkaline, no albumin, no casts. 


3.30 


2.0 


Same. 


3.45 


18.0 


Clearing, neutral, no albumin, no casts. 


4.00 


38.0 


Same. 


4.15 


56.0 


Clear as water, neutral, no albumin, no casts. 


4.30 


51.0 


Same. 


4.42^ 




Injection ended. 


4.45 


38.0 


Same. 


5.00 


18.0 


Same. 


5.15 


3.2 


Same. 



Animal released in good condition. 

Total urine in two-hour period since beginning of inj action, 224.2 cc. 
Feces, 16 grams. 

The diuretic action of salts with different acid radicals is shown 
in Figs. 112 and 113. In both figures the sodium chlorid curve, 
constructed from Experiment 26, is introduced as a control. 
If the sodium chlorid is entirely or partly replaced by another 
sodium salt, we find the effect on urinary secretion to be as 
follows: 



ABSORPTION, SECRETION— COMPLEX ORGANISM 343 



Salt. Urine in cc. 

Sodium Chlorid ' 127.5 

Sodium Nitrate... 129.4 

Sodium Bromid 181.3 

Sodium Acetate 182 

Di-Sodium Hydrogen Phosphate 184.2 

Sodium Di-Hydrogen Phosphate 204.4 

Sodium Iodid 237.5 

Sodium Sulphate 247 




Figure 112. 



Figure 113. 



344 



(EDEMA AND. NEPHRITIS 



With the exception of the nitrate and the iodid, the diuretic 
action of the acid radicals parallels completely their dehydrating 
effect upon (protein) colloids. In the amount and concentration 
employed the nitrate shows a markedly poisonous effect. This 
is possibly the reason why it stands lower in the series than we 
should expect. The iodid, on the other hand, stands unexpectedly 
high. But as we employed a higher concentration of the iodid 
than of the acetate, the phosphate or the sulphate, the use of a 
greater absolute amount of the iodid more than compensated 
for its less powerful action. 

The curves of Figs. 112 and 113 are constructed from Experi- 
ments 26, 27, 28, 29, 30, 31, 32 and 33. 

Experiment 26. Injection Fluid: m/4 NaCl. White male 
rabbit J. Weight 2169 grams. Kept on standard mixed diet. 175 
cc. of the above solution are injected into ear vein at uniform rate 
of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


12.00 




Tied down, catheterized, injection begun. 




5.0 


Cloudy, alkaline, no albumin, no casts. 


12.15 


1.0 


Same. 


12.30 


7.0 


Clearing, otherwise the same. 


12.45 


10.0 


Same. 


1.00 


17.0 


Same. 


1.15 


29.0 


Same. 


1.27^ 




Injection ended. 


1.30 


38.5 


Same. 


1.45 


12.0 


Same. 


2.00 


13.0 


Same. 



Animal released in good condition. 

Total urine in two-hour period since beginning of injection, 127.5 cc. 



Experiment 27. Injection Fluid: m/4 NaN0 3 . White and 
Belgian female rabbit. Weight 1393 grams. Kept on standard mixed 
diet. 175 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


3.00 




Tied down, catheterized, injection begun. 




0.5 


Yellow, alkaline, no albumin, no sugar, no casts. 


3.15 


1.4 


Same. 


3.30 


9.6 


Same. 


3.45 


23.0 


Clear as water, otherwise the same. 


4.00 


36.0 


Same. 


4.15 


37.0 


Clear, neutral, trace of albumin, sugar present, red blood 






corpuscles, no casts. 


4.27J^ 




Injection ended. 


4.30 


16.0 


Same. 


4.45 


5.4 


Same. 


5.00 


1.0 


Clear, alkaline, no albumin, sugar present, no casts. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 345 



Animal released. 

Total urine in two-hour period since beginning of injection, 129.4 cc. 
For some hours after its release the animal seems exhausted and takes 
no food. Next morning is again in good condition. 

Experiment 28. Injection Fluid: m/4 Sodium Bromid. White 
and Belgian female rabbit. Weight 1393 grams. Kept on standard 
mixed diet. 

175 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


11 


00 


1.0 


Tied down, catheterized, injection begun. 
Clear, yellow, alkaline. 


11 


15 


2.8 


Yellow, alkaline, traces of albumin, no sugar, many blood 
cells, many casts. 


11 


30 


20.5 


Same. 


11 


45 


23.0 


Clear as water, alkaline, faint trace of albumin, no sugar, 
occasional casts. 


12 


00 


38.0 


Clear, alkaline, very faint trace of albumin, sugar present, 
no casts. 


12 


15 


34.0 


Same. 


12 


27 y 2 




Injection ended. 


12 


30 


36.0 


Same. 


12 


45 


17.0 


Same. 


1 


00 


10.0 


Same. 



Animal released in sleepy condition. 

Total urine in two-hour period since beginning of injection, 181.3 cc. 



Experiment 29. Injection Fluid: 100 cc. m/4 NaCl+100 cc. 
m/4 Sodium Acetate. White male rabbit J. Weight 2419 grams. 
Kept on standard mixed diet. 

175 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


2.45 




Tied down, catheterized, injection begun. No urine. 


3.00 




No urine. 


3.15 


33.0 


Clear, alkaline, no albumin, no sugar, no casts. 


3.30 


31.0 


Same. 


3.45 


34.0 


Same. 


4.00 


34.0 


Clear, alkaline, no albumin, trace of sugar, no casts. 


4.12^ 




Injection ended. 


4.15 


36.0 


Same. 


4.30 


8.0 


Same. 


4.45 


6.0 


Same. 



Animal released in good condition. 

Total urine in two-hour period since beginning of injection, 182 cc. 



346 



(EDEMA AND NEPHRITIS 



Experiment 30. Injection Fluid: 180 cc. m/4 NaCl-f-20 cc. m/4 
Na 2 HP0 4 . Yellow and white male rabbit. Weight 1444 grams. 
Kept on standard mixed diet. 

175 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


11.45 




Tied down, catheterized, injection begun. 




5.5 


Thick, yellow, alkaline, no albumin, no sugar, no casts. 


12.00 


1.5 


Clearing, otherwise the same. 


12.15 


5.2 


Same. 


12.30 


27.0 


Same. 


12.45 


41.0 


Same. 


1.00 


42.0 


Clear as water, faintly alkaline, no albumin, trace of 






sugar, no casts. 


1.12^ 




Injected ended. 


1.15 


37.5 


Same. 


1.30 


20.0 


Same. 


1.45 


10.0 


Same. 



Animal released. Found dead in cage next morning. 

Total urine in two hour-period since beginning of injection, 184.2 cc. 

Experiment 31. Injection Fluid: 180 cc. m/4 NaCl-f-20 cc. 
m/4 NaH 2 P0 4 . Black male rabbit C. Weight 2277 grams. Kept on 
standard mixed diet. 

175 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine 


in cc. 


Remarks. 


11.30 




Tied down, catheterized, injection begun. 
Yellowish-brown, alkaline, no albumin, no sugar, no 
casts. 


8 


.6 


11.45 


1 


8 


Same. 


12.00 


12 


5 


Clearing, otherwise the same. 


12.15 


33 


5 


Same. 


12.30 


52 





Same. 


12.45 


60 





Clear as water, faintly alkaline, no albumin, trace of 
sugar, no casts. 


12.573^ 
1.00 






Injection ended. 
Same. 


36 





1.15 


7 





Same. 


1.30 


1 


6 


Same. 



Animal released in good condition. 

Total urine in two-hour period since beginning of injection, 204.4 cc. 



Experiment 32. Injection Fluid: m/4NaI. Black male rabbit C. 
Weight 2539 grams. Kept on standard mixed diet. 

175 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 347 



1 lme. 


• 

Urine 


in cc. 


Remarks. 


3. 15 






Tied down, catheterized, injection begun. 




4 





Thick, amber, alkaline, no albumin, no sugar, no casts. 


3.30 


1 





Same. 


3.45 


15 





Same. 


4. 00 


to 




Clear, neutral, no albumin, trace of sugar, no casts. 


4.15 


40 





Same. 


,4.30 


42 


5 


Same. 


4.42^ 






Injection ended. 


4.45 


48 





Same. 


5.00 


30 





Same. 


5.15 


18 





Same. 



Animal released. 

Total urine in two-hour period since beginning of injection, 237.5 cc. 
Animal found dead in cage three days later. 

Autopsy: Decomposition advanced. Hemorrhagic spots observed 
in kidney. 



Experiment 33. Injection Fluid. 100 cc. m/4 NaCl+100 cc. 
m/4 Na 2 S0 4 . White male rabbit P. Weight 2670 grams. Kept on 
standard mixed diet. 

175 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


10.30 




Tied down, catheterized, injection begun. 




4.3 


Clear, amber, acid, no albumin, no sugar, no casts. 


10.45 


2.4 


Same. 


11.00 


33.6 


Clear as water, neutral, no albumin, no sugar, no casts. 


11.15 


38.0 


Same. 


11.30 


43.0 


Same. 


11.45 


47.0 


Same. 


11.57^ 




Injection ended. 


i2.00 


58.0 


Clear, no albumin, trace of sugar, no casts. 


12.15 


16.0 


Same. 


^12.30 


9.0 


Same. 



Animal released in good condition. 

Total urine in the two-hour period since beginning of injection, 
247 cc. 



Salts made up of a powerfully dehydrating base with a power- 
fully dehydrating acid have, of course, the most effect upon 
protein colloids. Magnesium sulphate is an example of such a 
combination. Therefore, if our theory is true, we should expect 
this salt to produce a greater diuresis than any yet described. 
That this is actually the case is shown by the curve of Fig. 114 
as well as the corresponding Experiment 34. With injection 
of magnesium sulphate we obtained a urinary output of 300 cc. 



348 



(EDEMA AND NEPHRITIS 



Experiment 34. Injection Fluid: 180 cc. m/4 NaCl+20 cc. m/4 
MgS0 4 . White male rabbit J. Weight 2407 grams. Kept on standard 
mixed diet. 



175 cc. of the above solution are injected into ear vein at uniform rate 
of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


10.45 




Tied down, catheterized, injection begun. 




45.0 


Cloudy, yellow, alkaline, no albumin, no sugar, no casts. 


11.00 


16.0 


Same. 


11.15 


44.0 


Almost as clear as water, alkaline, no albumin, trace of 






sugar, no casts. 


11.30 


45.0 


Clear as water, faintly alkaline, no albumin, much sugar, 






no casts. 


11.45 


46.5 


Same. 


12.00 


51.5 


Same. 


12.12J^ 




Injection ended. 


12. 15 


59.0 


Same. 


12.30 


21.0 


Same. 


12.45 


17.0 


Same. 



Animal released in good condition. 

Total urine in two-hour period since beginning of injection, 300 cc. 



The analogies between these various experimental facts on 
the secretion of urine, and the model previously described and 
constructed with a view to elucidating some of these facts need 
no special comment. In our model we have eliminated the 
colloids of the blood stream, and a colloid reservoir of water 
corresponding with the water-saturated body colloids, by work- 
ing with simple salt solutions only. As our considerations 
have shown, the colloids of the blood and of the tissues generally 
play a part in urinary secretion in so far as they furnish storage 
places for water which is liberated under the conditions employed 
in the described experiments on diuresis. Our model, therefore, 
illustrates particularly the changes that occur in the kidney 
(which represents physico-chemically only a much folded col- 
loid membrane). In our model the " secretion " of " urine " 
is induced through a hydrostatic pressure which forces a liquid 
through the capillary bed formed by the powdered fibrin. W 7 hen 
an acid is brought in contact with the fibrin it swells, closes the 
capillary pores, and in proportion to the amount of this closure 
a formerly effective hydrostatic pressure becomes less and 
less capable, or, finally, even entirely incapable of forcing any 
liquid through this bed. We can counteract the effect of this 
acid by various salts, wherein again we find the saline diuretics 
to be more effective than certain other common salts. Such 



ABSORPTION, SECRETION — COMPLEX ORGANISM 349 



a salt as sodium sulphate, of course, makes the fibrin shrink 
more than an equally concentrated sodium chlorid, and so the 
former, by increasing the size of the capillary pores, more than 
the latter favors an increased " secre- 
tion " in our model. Matters in the 
living kidney need not of course, be 
quite so simple though if the kidney 
colloids have a physical constitution 
at all comparable to that of the more 
solid hydrophilic soap colloids (and 
much evidence points in this direc- 
tion) the model which has been de- 
scribed with those to be touched 
upon later 1 really come closer to the 
whole truth than might at first sight 
seem possible. 

6. On the Colloid-chemistry of 
Sugar Diuresis 2 

While the various non-electrolytes 
as compared with the electrolytes 
do not produce a great dehydration 
of protein colloids, some of them 
exhibit considerable activity in this 
regard, notably the sugars. The ex- 
periments which follow reveal their 
similar dehydrating action upon the 
whole "living" animal. They there- 
fore do away with the belief of various 
authors that the dehydrating effects 
of non-electrolytes on tissues and 
organisms as a whole, furnish sup- 
port for the " osmotic " theory of 
water absorption. At the same time 

the absurd view is again met that although the colloid-chemical 
theory explains water absorption in dead tissues its laws do not 

1 See pages 371 and 380. 

2 Martin H. Fischer and Anne Sykes: Science, 38, 486 (1913); Kolloid- 
Zeitschr., 14, 223 (1914). 




Hours 1 
Figure 114. 



(EDEMA AND NEPHRITIS 




Hours 1 
Figure 115. 



hold for living animals; for it need 
scarcely be said that our rabbits were 
alive. 

It will now be shown that the diuretic 
action of the sugars parallels their dehy- 
drating effect on protein colloids, <md 
that like the diuretic salts previously 
discussed, the sugars owe their action 
primarily not to any effect upon the 
kidney, but to an effect upon all the 
tissues of the body generally. With 
any sugar the degree of diuresis, in- 
creases with every increase in the 
concentration. When we compare the 
degree of increase in urinary output 
with that in concentration we find, 
roughly, that doubling the concentra- 
tion of sugar more than doubles the 
urinary output. This is just the re- 
verse of what happens with salt solu- 
tions where the lower concentrations 
produce relatively greater effects than 
the higher. This difference in the 
behavior of sugars and of salts upon 
rabbits parallels their effects upon 
simple protein colloids. At the same 
concentration the three sugars produce 
different degrees of diuresis just as 
they bring about different degrees of 
dehydration in gelatin or fibrin, dex- 
trose and levulose standing very close 
together, while saccharose is far more 
powerful. 

Figs. 115, 116 and 117 present in 
graphic form the results obtained from 
Experiments 35, 36, 37, 38, 39, 40, 41, 
42, 43, 44, 45 and 46. 

Experiment 35. Injection Fluid: 4/m 
dextrose. Gray rabbit R. Weight 2500 
grams. Kept on standard mixed diet. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 




352 



(EDEMA AND NEPHRITIS 



150 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



Time. 


• 

L rine in cc. 


Remarks. 


2.15 




Tied down, catheterized, injection begun. 




15.0 


Yellow, alkaline, no albumin, no casts. 


2.30 


A few drops 


Same. 


2.45 


4.5 


Same. 


3.00 


4.5 


Same. 


3.15 


4.0 


Clear, neutral, no albumin, no casts. 


3.30 


10.0 


Same. 






Injection ended. 



Animal released in good condition. 

Total unrine in one and one-quarter-hour period since beginning 
of injection, 23 cc. 

Experiment 36. Injection Fluid: m/2 dextrose. White rabbit T. 
Weight 1600 grams. Kept on standard mixed diet. 

150 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in jjc. 


Remarks. 


11.15 




Tied down, catheterized, injection begun. 




0.5 


Yellow, alkaline, no albumin,, no casts. 


11.30 


3.0 


Same. 


11.45 


12.0 


Clear as water, alkaline, no albumin, no casts. 


12.00 


19.0 


Same. 


12.15 


21.0 


Same. 


12.30 


24.0 


Same. 






Injection ended. 


12.45 


17.0 


Same. 


1.00 


9.0 


Same. 


1.15 


6.0 


Same. 



Animal released in good condition. 

Total unrine in two-hour period since beginning of injection, 111 cc. 



Experiment 37. Injection Fluid: 3/4 m dextrose. Gray rabbit 
R. Weight 2500 grams. Kept on standard mixed diet. 

150 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


2.30 




Tied down, catheterized, injection begun. 




30.5 


Yellow, alkaline, no albumin, no casts. 


2.45 


3.0 


Clearing, alkaline, no albumin, no casts. 


3.00 


10.0 


Clear as water, alkaline, no albumin, no casts. 


3.15 


42.0 


Same. 


3.30 


46.0 


Same. 


3.45 


57.0 


Same. 






Injection ended. 


4.00 


33.0 


Same. 


4.15 


3.5 


Same. 


4.30 


2.0 


Same. 



Animal released in good condition. 

Total urine in two-hour period since beginning of injection, 230.5 cc. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 353 



Experiment 38. Injection Fluid: m/1 dextrose. Belgian hare. 
Weight 1534 grams. Kept on standard mixed diet. 

150 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


11.30 




Tied down, catheterized, injection begun. No urine. 


11.45 


25.0 


Clear, neutral, no albumin, no casts. 


12.00 


78.0 


Same. 


12.15 


62.0 


Same. 


12.30 


45.0 


Same. 


12.45 


50.0 


Neutral, traumatic red blood corpuscles, no casts. 






Injection ended. 






Animal released shivering and with teeth chattering. 


1.10 




Dies. 



Autopsy: Everything negative. Cavities empty; tissues dry; 
petechial hemorrhages in membrane of urethra and bladder. Kidney, 
pelvis and ureter uninjured. 

Total urine in one and one-quarter hour period since beginning of 
injection, 262 cc. 



Experiment 39. Injection Fluid: m/4 levulose. Yellow rabbit 
Smutty. Weight 2250 grams. Kept on standard mixed diet. 

150 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


2.30 




Tied down, catheterized, injection begun. 






No urine. 


' 2.45 




No urine. 


3.00 


3.5 


Cloudy, alkaline, no casts. 


3.15 


5.5 


Same. 


3.30 


5.5 


Same. 


3.45 


10.0 


Same. 






Injection ended. 


4.00 


9.0 


Same. 


4.15 


4.0 


Same. 


4.30 


5.0 


Same. 



Animal released in good condition. 

Total urine in two-hour period since beginning of injection, 41.5 cc. 

Experiment 40. Injection Fluid: m/2 levulose. White rabbit B. 
Weight 1700 grams. Kept on standard mixed diet. 

150 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



354 



(EDEMA AND NEPHRITIS 



Time. 


Urine in cc. 


Remarks. 


11 30 




x 1PQ down, C8fvu6u6in.z6ci| injection ocgun. 




9.0 


"Vpllnxc filVcili'np nn nlltiiTniTi Tin paq+q 
j. ciiu » , di-Cv-diiiic:, l±\J a i ij Li nil n , Liu taots. 


11.45 


5.0 


Clear as water, otherwise the same. 


12.00 


20.0 


Same. 


12.15 


30.0 


Same. 


12.30 


31.0 


Same. 


12.45 


35.0 


Same. 






Injection ended. 


1.00 


15.0 


Same. 


1.15 


7.0 


Same. 


1.30 


4.0 


Same. 



Animal released in good condition. 

Total urine in two-hour period since beginning of injection, 147 cc. 



Experiment 41. Injection Fluid: 3/4 m levulose. Brown and 
white rabbit. Weight 1750 grams. Kept on standard mixed diet. 
150 cc. of the above solution are injected into ear vein at uniform 



rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


11.45 




Tied down, catheterized, injection begun. 




12.0 


Yellow, alkaline, no albumin, no casts. 


12.00 


22.0 


Clear, alkaline, no albumin, no casts. 


12.15 


40.0 


Same. 


12.30 


42.0 


Same. 


12.45 


50.0 


Same. 


1.00 


45.0 


Same. 






Injection ended. 


1.15 


17.0 


Same. 


1.30 


10.0 


Same. 


1.45 


7.0 


Same. 



Animal released. Found dead in cage next morning. 

Total urine in two-hour period since beginning of injection, 233 cc. 



Experiment 42. Injection Fluid: m/1 levulose. Black rabbit V. 
Weight 1530 grams. Kept on standard mixed diet. 

150 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


3. 15 




Tied down, catheterized, injection begun. 




2.0 


Yellow, alkaline, no albumin, no casts. 


3.30 


38.0 


Clear, neutral, no albumin, no casts. 


3.45 


72.0 


Same. 


4.00 


62.0 


Same. 


4.15 


54.0 


Same. 


4.30 


47.0 


Same. 






Injection ended. 


4.45 


17.0 


Same. 


5.00 


12.0 


Same. 


5.15 


2.0 


Same. 



Animal released. Dies in a short time. 

Total urine in two-hour period since beginning of injection, 306 cc. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 355 



Experiment 43. Injection Fluid: m/ 4 saccharose. Yellow rabbit 
Smutty. Weight 2250 grams. Kept on standard mixed diet. 

150 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


2.45 




Tied down, catheterized, injection begun. 




6.0 


Yellow, alkaline, no albumin, no casts. 


3.00 


3.0 


Same. 


3.15 


22.0 


Clear, neutral, no albumin, no casts. 


3.30 


22.0 


Same. 


3.45 


23.0 


Same. 


4.00 


25.0 


Same. 






Injection ended. 


4.15 


15.0 


Same. 


4.30 


11.0 


Same. 


4.45 


9.0 


Same. 



Animal released in good condition. 

Total urine in two-hour period since beginning of injection, 130 cc. 



Experiment 44. Injection Fluid: m/2 saccharose. Belgian rab- 
bit H. Weight 1800 grams. Kept on standard mixed diet. 

150 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


2.45 




Tied down, catheterized, injection begun. 
Yellow alkaline, no albumin, no casts. 


10.0 


3.00 


23.5 


Clear as water, neutral, no albumin, no casts. 


3.15 


73.5 


Same. 


3.30 


61.0 


Same. 


3.45 


59.0 


Same. 


4.00 


41.0 


Same. 

Injection ended. 


4.15 


24.0 


Same. 


4.30 


10.0 


Same. 


4.45 


3.0 


Same. 



Animal released limp and shaking. Next morning alive and well. 
Five days later alive and well. 

Total urine in two-hour period since beginning of injection, 295 cc. 



Experiment 45. Injection Fluid: 3/4 m saccharose. Yellow 
rabbit Sammy. Weight 2250 grams. Kept on standard mixed diet. 

150 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



356 



(EDEMA AND NEPHRITIS 



Time. 


Urine in cc. 


Remarks. 


12.00 




Tied down, catheterized, injection begun. 






No urine. 


12. 15 


10.5 


Clear, neutral, no albumin, no casts. 


12.30 


63.0 


Same. 


12.45 


74.0 


Same. 


1.00 


87.5 


Same. 


1.15 


38.0 


Same. 






Injection ended. 


1.30 


36.0 


Same. 


1.45 


18.0 


Same. 


2.00 


16.0 


Same. 



Animal released. Found dead in cage next morning. 

Total urine in two-hour period since beginning of injection, 343 cc. 



Experiment 46. Injection Fluid: m/1 saccharose. Black rabbit U. 
Weight 1500 grams. Kept on standard mixed diet. 

90 cc. of the above solution are injected into ear vein at uniform 
rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


3.15 




Tied down, catheterized, injection begun. 






No urine. 


3.30 


32.5 


Clear, neutral, no albumin, no casts. 


3.45 


75.0 


Same. 


4.00 


56.5 


Same. 


4.05 




Animal dies. 



When we compare the diuretic action of the sugars with 
that of the salts we note the same interesting differences as 
when these two classes of substances are compared in their 
effect upon the dehydration of protein colloids. Thus, when 
the same amount of differently concentrated salt solutions 
(sodium chlorid, for example), is injected intravenously 1 a rela- 
tively greater effect is produced by the weaker solutions than 
by the more concentrated, while just the reverse is the case 
when the sugars are used. This is clearly apparent in the fol- 
lowing table : 2 

x See page 331: also the first edition of " (Edema" and James J. Hogan 
and Martin H. Fischer: Kolloidchem. Beihefte, 3, 385 (1912). Martin H. 
Fischer and Anne Sykes: Science, 37, 845 (1913); Kolloid-Zeitschr., 13, 
112 (1913). 

2 It should be remembered that owing to dissociation m/8 NaCl solution 
is " osmotically " almost equivalent to an m/4 solution of a non-electrolyte. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 357 



NaCl. 


Dextrose. 


Levulose. 


Saccharose. 


m/8 68.9 cc. 


m/4 23 cc. 


m/4 40 cc. 


m/4 130 cc. 


m/4 159 cc. 


m/2 111 cc. 


m/2 147 cc. 


m/2 295 cc. 




3/4 m 230.5 cc. 


3/4 m 231 cc. 


3/4 m 343 cc. 


m/2 288.5 cc. 









The table also shows how tremendously saccharose dehy- 
drates. Easy as it is to understand on a colloid basis these 
differences between the sugars or between the sugars and the 
electrolytes, equally impossible is it to interpret them or any 
" osmotic " ground. 

With these experiments we think that the colloid-chemical 
theory of water absorption and secretion by protoplasm has 
answered the last objections of those who oppose its claims to 
be considered the dominant if not the only factor in this problem. 

We believe that on the basis of the dehydrating effect of 
dextrose upon the tissues can be understood the dryness of the 
diabetic's tissues and his thirst, as well as the increased urinary 
output observed resulting from the excessive consumption of 
water in response to this thirst. A therapy which decreases 
the amount of circulating sugar in the diabetic organism (with- 
out increasing an " acidosis") 1 decreases thirst, water consump- 
tion and urinary output. 

7. Discussion of the Mechanism of Water Secretion by the 
Kidney. Some General Conditions Influencing Water 
Output.. Diuretics of the Second Order. 

In the evidence thus far presented, which has shown that an 
output of water by the kidney is possible only as free water is 
brought to it and in proportion to the amount of water thus 
brought, we have tacitly assumed that the kidney will always 
be capable of secreting the water when thus offered it just as in the 

1 What annoys and what kills a diabetic is not generally understood by 
even the recognized authorities who write on this subject. Thirst and 
polyuria are annoying and are controlled by controlling the starch and sugar 
intake of the individual; an acid intoxication dependent upon improper 
utilization or too great intake of fat is what kills and too great carbohydrate 
restriction is more to be feared in this connection than the reverse. See 
the remarks on "acidosis" on page 780. Also Martin H. Fischer: Prac- 
tical Urinalytic Methods and their Significance in Tice's Practice of Medicine 
1, 423, New York (1920). 



358 



(EDEMA AND NEPHRITIS 



model of urinary secretion previously described. We have, in a 
certain sense, committed ourselves to the view that the secretion 
of water is a relatively passive affair in that the kidney parenchyma 
acts as a mere -filtration membrane through which the water is 
squeezed under the influence of the blood pressure. In secreting 
the water, the kidney need not, however, play such a purely passive 
role. It is held by various authors that in order to transport the 
water from the blood out into the uriniferous tubules the kidney 
does work. If this be true then in order to get a normal urinary 
output the kidney must not only have free water at its disposal, 
but must also be able to do the necessary secretory work. We 
have now to discuss the evidence which has been brought forward 
to support these views. 

The proofs commonly adduced to show that the kidney in 
secreting water actually does work are as follows: there is, first, 
the old observation that the venous blood returning from an active 
kidney as well as the urine coming from it have a higher tempera- 
ture than the arterial blood entering it. Second stand the 
findings of J. Barcroft and T. G. Brodie 1 that an actively 
secreting kidney uses more oxygen and gives off more carbonic 
acid than a resting one, and that the amount of oxygen thus con- 
sumed and the amount of carbonic acid thus produced rises hand 
in hand with the amount of water secreted. Thirdly, E. Heilner 2 
has found that when the urinary output in starving dogs and 
rabbits is increased by forcing water the carbonic acid elimination 
is increased. To use a homely simile, such observations are 
intended to prove that fuel is consumed in order to get the energy 
necessary for a separation of water from the kidney. As in any 
machine which makes possible such energy transformations 
many totally different causes may interfere with its smooth run- 
ring, so also in the kidney many different and apparently discon- 
nected agencies may serve to interfere with the normal energy 
transformations which permit a kidney to transport the free water 
offered it in the blood over into the uriniferous tubules. Let 
us for a moment consider some of these. 

As the quantitative and qualitative output from a machine 
is dependent upon the quantity and nature of the materials fed 

l J. Barcroft and T. G. Brodie: Journal of Physiol., 32, 18 (1904); , 
ibid., 33, 52 (1905). 

2 E. Heilner: Zeitschr. f. Biol., 49, 373 (1908). 



ABSORPTION, SECRETION— COMPLEX ORGANISM 359 



into it, so also the secretion of urine by the kidney is dependent 
in a striking way upon the circulation. Not only can the " nor- 
mal " secretion of urine be increased through changes in the 
circulation, but it can still more strikingly be decreased. From 
histological studies, and, on the whole, very hypothetical reason- 
ings, W. Bowman (1842) first laid stress on the importance of 
the pressure under which the blood flows through the kidneys 
as a factor in determining the secretion of urine. This pressure 
idea was further developed and given an experimental basis 
by Carl Ludwig (1884) and his pupils. Through their work 
considerable evidence was advanced to show that changes in 
blood pressure, no matter how induced, are always followed by 
changes in the amount of urine secreted, and, on the whole, 
in this sense, that an increase in blood pressure is accompanied 
by an increased urinary secretion, while a decrease in blood pres- 
sure is followed by an opposite result. This long-accepted belief 
met a setback in the critical studies of R. Heidenhain, 1 who 
showed that the parallelism between blood pressure and urinary 
secretion is by no means absolute. Not only does interference with 
the outflow of venous blood from the kidney — a condition asso- 
ciated with an increase rather than any decrease in blood pressure — 
lead to a fall in the amount of urine secreted easily equal to the 
fall encountered after interference with the arterial influx of blood, 
but various diuretics which do not alter the blood pressure are 
known to bring about a decided increase in urinary secretion. 
(Some of the saline diuretics belong in this group, the behavior 
of which we have already discussed.) Heidenhain maintained 
that the experimental facts available in his day were best har- 
monized by saying that the velocity with which the blood passes 
through the kidney determines the amount of urinary secretion. 
But further than this he did not go with any mechanical or, to 
put it more generally, physico-chemical concept of urinary secre- 
tion. 

In place of the teaching of Ludwig that a secretion of urine 
is primarily dependent upon a blood pressure, or Heidenhain's 
belief that the velocity with which the blood passes through the 
kidney is of primary importance, the experiments and clinical 
observations at hand on this subject are best interpreted by 

1 R. Heidenhain: Hermann's Handbuch d. Physiologie, 5, 309, Leipzig 
(1883). 



360 



(EDEMA AND NEPHRITIS 



saying that the normal urinary secretion is absolutely dependent 
upon an adequate oxygen supply to the cells constituting the 
parenchyma of the kidney. Any interference with this oxygen 
supply leads to a decrease in urinary secretion even to the point 
of absolute and permanent stoppage. Through a particularly 
favorable oxygen supply to the kidneys the secretion of urine may 
be increased above that ordinarily considered 11 normal." 

This interpretation meets with no experimental objections. 
Nature has seen to it that the kidneys shall not lack facilities 
for a plentiful supply of oxygenated blood by endowing them 
with strikingly large renal arteries. Any considerable inter- 
ference with the oxygen supply to the kidney is followed by a 
drop in urinary secretion. It does not matter how such an inter- 
ference is brought about. It may be brought about through a 
change in the action of the heart itself, such as a decrease either 
in the number or the force of the heart's contractions or both 
(vagus stimulation, myocarditis, valvular heart disease, dilata- 
tion). Or the deficiency in oxygen supply to the kidneys may 
be brought about through hemorrhage or through stimulation 
of vasomotor nerves whose effect tends, in the aggregate, to 
decrease the amount of oxygenated blood passing through the 
kidneys. Most effectively can the oxygen supply to the kidneys 
be diminished to any degree or be cut off entirely through com- 
pression of the renal artery from without (experimental ligation, 
clamping, tumor) or occlusion from within (arteriosclerosis, 
experimental or clinical embolism). The same result is accom- 
plished if the outflow of blood through the renal veins is suf- 
ficiently impeded (experimental ligation, tumor, passive con- 
gestion due to heart disease). 

An adequate oxygen supply to the kidney, on the other hand, 
favors the secretion of urine. This is evidenced by the fact that 
the removal of the various conditions outlined above (provided 
they have not acted too long) is followed by a reestablishment 
of the urinary secretion to normal. When special efforts are 
made to increase the oxygen supph- to the kidneys, as by ligating 
several of the larger arteries that pass off the aorta, or by stimulat- 
ing vasomotor nerves which tend to increase the quantity of 
oxygenated blood passing through the kidneys, a secretion of 
urine in excess of that considered normal may be obtained. 
On the other hand, the most liberal supply of poorh r oxygenated 



ABSORPTION, SECRETION— COMPLEX ORGANISM 361 



blood to the kidneys even without any other disturbance in the 
circulation (such as variations in blood pressure) is incapable of 
maintaining a normal secretion of urine even for a little while. 

On the basis of these facts we shall now be able to discuss 
and to understand the mode of action of certain drugs, exclusive 
of the saline diuretics, which are capable of increasing the out- 
put of water through the kidney. This second type of diuretic 
owes its action primarily to its power of favoring the oxygen supply 
to the kidney. 

It is readily appreciated that in liberating water from a tis- 
sue its degree of swelling is reduced. Pressure upon the blood 
vessels lying within an organ is thereby removed and a better 
blood flow through the organ favored. Secondarily, therefore, a 
diuretic salt also brings about a better blood supply to all the 
organs of the body, including the kidney. On the other hand, the 
diuretic drugs of the second order in favoring a better oxygen 
supply to the tissues of the body favor the removal of the acid 
products of normal and abnormal metabolism, and so incidentally 
they further diuresis by furnishing " free " water. 

We are also familiar with drugs which can decrease the out- 
put of water from the kidney. They act in a way the opposite of 
the diuretics of the second order. We can best begin our discus- 
sion with them. 

It is a familiar fact that after the administration of morphin 
or atropin or of chloroform, ether or alcohol, in any considerable 
amounts, there is always a fall in urinary secretion that may at 
times amount to complete suppression. It is possible for these 
substances to lead to such suppression through action upon the 
kidneys alone. Under ordinary circumstances such a purely 
local action is, however, not to be anticipated. In fact, it is 
perfectly possible for a temporary suppression of urine to follow, 
say, a general anesthetic, without any changes in the kidneys 
themselves. The administration of all these anesthetics and of 
certain alkaloids is accompanied by such a state of lack of oxygen 
in the tissues of the body generally, as we have before described for 
isolated organs. In consequence of this, the capacity of the 
colloids of all the tissues of the body (including the blood and 
the lymph) for holding water is increased above that considered 
normal. After administration of any of these drugs the body gen- 
erally, therefore, is holding on to its water with special avidity, so 



362 



(EDEMA AND NEPHRITIS 



that none is left over to be free in the blood and so be excreted through 
the kidneys. This condition of the tissues after an anesthetic 
or a dose of morphin, for example, is evidenced not only by the 
lack of urinary secretion, but by the thirst complained of by the 
patient. As the patient gets over his anesthetic his urinary 
secretion not only comes up, but his thirst disappears, even 
though no water has been given. 

To get the described results it will be remembered that con- 
siderable amounts of these various drugs have to be administered. 
Such doses lead to a state of lack of oxygen in the tissues. Small 
doses of ether, alcohol, etc., increase the urinary output. In try- 
ing to say how this effect is brought about we have to remember 
the favorable conditions for secretion that are induced in the 
kidneys when these are given plenty of oxygen (while at the same 
time their carbonic acid is being rapidly carried away). Such 
conditions are brought about through the increased frequency 
and force of the heart beat, the more rapid breathing and the 
vasodilatation that are induced by small doses of these drugs. 
A large part of the diuretic action of caffein and its various deriva- 
tives, as well as of digitalis, can also be understood on this basis. 
The drugs which make for an increased oxygen supply and a 
favored carbonic acid removal from the kidneys do the same 
for the body tissues generally. A decreased capacity of all the 
body colloids for holding water is, therefore, a natural result under 
such circumstances, in consequence of which water is liberated 
into the blood. This water then becomes available for urine. 
A dose of caffein or digitalis, therefore, not only puts the kidneys 
into a condition which favors the secretion of water by them, but 
at the same time aids in furnishing them water through an indirect 
effect upon the body colloids generally. 

These facts are of the greatest importance when we approach 
the practical problems of medicine, and we shall, therefore, return 
to discuss them further when we take up nephritis. 1 

8. Historical and Critical Remarks on Urinary Secretion 

We may apply a test to the reasoning of the preceding para- 
graphs by considering a few of the large number of valuable 
experimental studies available on the secretion of water by the 
kidney in the light of the ideas developed above. While the 

1 See page 667. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 363 



laboratory facts adduced by different authors harmonize well 
with each other their interpretation has been warmly debated. 

Let us begin by considering the results that have been obtained 
when various salt solutions have been injected directly into the 
blood. When a (" physiological ") 0.9 per cent sodium chlorid 
solution is injected into a rabbit, a secretion of urine is obtained 
which quickly equals the amount of salt solution infused. 
If a somewhat stronger salt solution is employed, more urine is 
secreted than is infused, and this difference between amount 
injected and amount excreted becomes the greater the higher the 
concentration of the sodium chlorid in the injection fluid. If 
the injections are very large, or are carried on for a long time, 
the absolute differences between amount infused and amount 
secreted remain, but the relative become less and less apparent. 1 
If no time limits are set upon the experiment^ the end results 
become somewhat complicated (though not confusing), owing 
to the fact that the animal develops the symptoms and signs of 
a general oedema. This oedema is due to the oxygen want 
from which the animal suffers whenever these great injections 
of salt solution are continued sufficiently long. 

Isosmotic solutions of the chlorids, bromids and iodids of 
sodium or potassium bring about approximately the same excre- 
tion of urine. 2 When, however, equally concentrated solutions 
of the various saline diuretics (phosphate, sulphate, tartrate 
or citrate of sodium) are injected, a much greater secretion of 
urine is obtained. 3 

How are these various experimental findings to be interpreted? 
Let us first call attention to the important experimental error 
that is introduced into any of these experiments if an anesthetic is 
used. When enough is used to produce anesthesia, a lack of ox- 
ygen in the tissues and a retention of some of the liquid infused 
may be expected to follow. The effect of an infusion is divis- 
ible into two parts: first, the effect of the water injected; second, 
the effect of the salt. Other things being equal, we may expect 

1 See Martin H. Fischer: University of California Publications, Physi- 
ology, 1, 107 (1904). 

2 von Limbeck: Arch. f. exp. Path. u. Pharm., 25, 89 (1888). 

3 Magnus: Arch. f. exp. Path. u. Pharm., 44, 68 and 396 (1900); Ueber 
Diurese, Heidelberg (1900). Torald Sollmann: Arch. f. exp. Path. u. 
Pharm., 46, 13 (1901). B. Haake and K. Spiro: Hofmeister's Beitrage, 2, 
149 (1902). 



364 



(EDEMA AND NEPHRITIS 



the water to behave, so far as diuresis is concerned, just as this be- 
haves when water only is injected. The salt injected has an effect 
upon the kidney and also upon the colloids of the body gen- 
erally, including those of the blood and lymph. As the chief 
salt of the body fluids is sodium chlorid, we are not surprised 
to find that a sodium chlorid solution " isosmotic " with the 
blood, when injected intravenously, yields in a short time an 
amount of urine about equal in volume to that of the salt solu- 
tion injected. If, however, a sodium chlorid solution having 
a concentration above that of the blood is used, an increased 
secretion of urine is obtained. This is because the salt acts 
not only directly upon the colloids of the blood and makes 
them liberate some of their water, but diffuses into the tissues 
of the body and makes the colloids here also give up a part of 
their water. This water is then " free/' and can be secreted 
as urine. The salt also acts upon the colloids of the kidney, 
making the cells of this organ shrink. This shrinkage of the 
kidney cells necessarily means a decrease in the pressure exerted 
upon the blood vessels passing through the kidney, and so a better 
blood flow through this organ is also favored. The higher the 
concentration of the injected salt the more water must the body 
tissues yield up for diuresis (and the better must also be the blood 
supply to the kidney). \ ~ 

We have no difficulty in understanding why isosmotic solutions 
of different salts are not equally effective in producing a diuresis. 
We have become familiar with the unequal effects of different 
salts on the absorption and secretion of water by colloids. Just 
as the sulphate, tartrate, phosphate and citrate of sodium are 
more effective in making fibrin or gelatin give up their water 
than the chlorid, bromid and iodid of this same metal, so are 
the former group expected to make the body colloids yield up 
a greater amount of water for diuresis than the latter. A similar 
difference of effect is to be expected upon the colloids constituting 
the kidney. The first-named group must tend to make this 
" shrink " more than the second. 

Let us see how well our theory fares if we apply it to the care- 
fully worked-out experiments of Ernst Frey. 1 This author - 
does not, of course, interpret his experiments as I have taken 
the liberty of doing for him, but on the more generally accepted 
1 Ernst Feey: Pfliiger's Arch., 120, 66 to 136 (3 papers) (1907). 



ABSORPTION, SECRETION— COMPLEX ORGANISM 365 



basis of alterations in the kidney and changes in blood pres- 
sure. 

Frey finds that when water is given a rabbit by mouth or 
rectum, or is injected intraperitoneally or into the small intestine, 
an increased amount of urine is secreted by the kidneys. I 
would say that this is because the tissues of the rabbit are satu- 
rated with water and so none of it is retained. If in place of 
water, a sodium chlorid solution is injected, the same or even 
a greater diuresis is obtained. This diuresis is the greater the 
higher the concentration of the salt solution injected (the amount 
of fluid injected being the same), just as in our own experiments 
already described. 

The diuresis following the introduction of water does not occur 
if any anesthetic is administered (morphin, chloral, ether, ure- 
thane). This is evidently because the anesthetics all produce 
a state of lack of oxygen, so that the tissues have an increased 
capacity for holding water and so do not secrete that which has 
been absorbed from the alimentary tract or peritoneum. Let 
Frey's finding be noted that these anesthetics do not interfere 
with the absorption of water from the gastro-intestinal tract. 
We are not surprised in the face of our explanation to note that 
Frey found this retention of water to occur just the same whether 
he had previously bled the animal or had cut the nerves to the 
kidneys, or changed the posture of the animal. Not even when 
he gave phloridzin or salicylic acid in an attempt to " stimulate " 
the kidneys did he get a urinary flow. According to our ideas 
of urinary secretion such results are entirely to be expected. None 
of these procedures affect the hydration capacity of the colloids 
of the tissues except as some increase it. 

The continuance of an absorption of water from the gastro- 
intestinal tract while none is being secreted through the kidneys 
is easily explained by the increased hydration capacity of the body 
colloids induced through the effects of the anesthetics. 

9. Transition from the Physiological to the Pathological in Kidney 

Function 

One does not pass from the physiological to the pathological 
in a jump, but insensibly. Thus, the " normal " absorption of 
water by a cell is ordinarily regarded as subject to well-defined 



366 



(EDEMA AND NEPHRITIS 



variations, and yet as we approach the physiological extremes of 
high normal turgor we are likely to be halted by the information 
that we have already wandered into the regions of the patholog- 
ical and are face to face with an " oedema." The same holds 
true of all other functions. When in physiology we speak of a 
diminished urinary output we have really gotten into a region 
which others will call pathology. These paragraphs will show how 
the physiology and pathology of function as observed in the 
kidney fade inseparably into each other. 

We noted above how a series of most dissimilar disturbances 
in the circulation to the kidneys are in effect all the same in that 
they lead to a decreased output of water from the kidney. We 
have to say now what is the change wrought in the kidneys 
through the lack of oxygen which is produced in common by 
all of them. This is a question that we have argued many times 
before. Not only do we have an abnormal accumulation of 
carbonic acid in any organ when the blood flow through it is cut 
down, but through the interference with the oxygen supply to 
the part we expect an abnormal accumulation and production 
of various other acids in the affected tissues. Since the tissues 
contain various (hydrophilic) protein colloids we may expect 
these to swell if only a source of water is present. It is not 
surprising, therefore, that oncometric measurements have shown 
that every interference with the normal blood supply to the kidneys 
is followed by an enlargement of the organ, independently of any 
increase in size that may be due to mere filling of the vessels with 
blood. 1 No further comment is necessary to show how these 
observations and our previously detailed experiments on the 
cedema of passively congested parenchymatous organs dovetail. 2 

The lack of oxygen induced in the kidneys through circulatory 
disturbances makes itself felt in the end in the oxidation chem- 
istry of the kidney cells themselves. Now various chemical 
means are at our disposal by which we can interfere with the 
oxidations that occur normally in the kidney parenchyma 
without in any way altering the circulation of the kidney itself. 
We need mention only the effect of uranyl nitrate and various 

1 See Gottlieb and Magnus: Arch. f. exp. Path. u. Pharm., 45, 223 
(1901). The earlier contradictory results of Starling are open to question. 
E. H. Starling: Journal of Physiol., 24, 317 (1899). 

2 See page 268. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 367 

other metallic poisons, amyl nitrite, the cyanids and in lesser 
degree the various anesthetics, such as morphin, chloroform and 
ether. Every member of this list, which with varying degrees 
of ease is known to lead to albuminuria, hematuria, partial or 
complete suppression of urine, enlargement of the kidney and 
various " degenerative " changes in this organ considered char- 
acteristic of " nephritis," is known to interfere with the normal 
oxidations occurring in living tissues. The bearing that these 
remarks have on a large number of nephritides, encountered 
clinically, is apparent not only from the fact that almost every 
one of the poisons here mentioned has been known to lead to 
nephritis in man, but by the additional fact that the " toxic *' 
nephritides that appear in the course of various acute infections 
also belong to this group. 

When the oxygen supply to a kidney is cut off sufficiently, 
or that which passes into it cannot be used properly, albumin, 
and at times blood, appears in the urine. Such an albuminuria 
and hematuria may be made to subside if the condition leading 
to the lack of oxygen is removed after not too long a time. When 
now, we add to these facts of changes in circulation, increase 
in the size of the kidneys, progressive diminution in urinary 
secretion to the point of absolute stoppage, albuminuria, and 
hematuria, the further fact that on section the kidney parenchyma 
appears swollen, grayish, and with kidney markings obscured, 
we have no difficulty in recognizing that we are dealing with a 
series of changes that characterize the ordinary acute parenchy- 
matous nephritis. To this question we return in detail later, 
but it is brought up here to emphasize the fact that the changes 
occurring in these experimentally induced nephritides are in part 
analyzable, and so help not only toward a theoretical under- 
standing of what is observed in clinical cases of acute nephritis, 
but in so doing give promise of being of practical worth. 

10. The Secretion of Dissolved Substances 

We shall enter into the problem of the secretion of dissolved 
substances only sufficiently to point out the illuminating touch 
given it by the physical chemistry of the colloids. Great pessim- 
ism still reigns regarding our ultimate ability to explain, on a 
purely physico-chemical basis, all the phenomena of secretion. 



368 



(EDEMA AND NEPHRITIS 



That such a view is not justified must appear from even the brief 
remarks that follow. 

What has been most difficult to explain in secretion has been 
its selective character; in other words, the ability of the kidney, 
for example, to separate from the blood a liquid which has a totally 
different quantitative and qualitative composition. Qualitative 
differences are for the most part explainable through chemical 
changes that occur in the secretory cells themselves, whereby 
substances are produced (such as mucin for example) which do 
not appear in the blood at all. In other respects a secretion 
differs only in quantitative composition from the blood. This may 
go to the point of having almost entirely absent from a secretion 
certain constituents of the blood, as, for example, albumin from 
the urine. For the most part, however, the secretion contains 
some substances in higher, others in lower, concentration than 
the blood. To limit ourselves again to the urine, we need by 
way of illustration only recall that, under ordinary circumstances, 
the urine contains less chlorids than the blood, and more sul- 
phates and urea. How are such differences to be explained? 

To begin with, it is well to call to mind that a secretion of 
dissolved substances is possible only so long as water is furnished 
the living organism. A secretion of water is necessary before 
we can hope to have any secretion of dissolved substances. This 
is a physiological truth that is utilized daily by the intelligent 
physician when he orders the drinking of large amounts of water 
to aid the organism in ridding itself of any poison, as the toxin 
of an infectious disease, for example. How the secretion of water 
by the kidney may be made a continuous affair we have learned 
from our previous discussion. How it must make for a con- 
tinuous secretion of dissolved substances is apparent from what 
follows. 

Let us recall here our division of the urinary secretory system 
into its three parts: the blood, the secreting membrane, and the 
urine, and our brief characterization of the first as a liquid colloid 
in which various crystalloids are dissolved, the second as a solid 
colloid also containing various crystalloids, and the third as a 
watery solution of various crystalloids (practically) free from 
colloids. Thus far our discussion has shown that under the 
conditions normally existing in the body no water can be intro- 
duced into the blood without getting the secretion of an equal 



ABSORPTION, SECRETION— COMPLEX ORGANISM 369 



amount as urine. And what is secreted as urine is water, and only 
secondarily do substances come to be dissolved in it, so that it assumes 
a chemical composition which permits it to be characterized as urine. 
Let us see now what must happen if some soluble 1 (or pseudo- 
soluble) substance is introduced into the blood. To simplify 
the problem and not make our discussion unnecessarily long, let 
us think of the blood as one homogeneous system, and the 
urinary membrane as another. Under such circumstances one 
of three possibilities presents itself from a physico-chemical 
standpoint. The dissolved substance may distribute itself uni- 
formly throughout the blood and the urinary membrane, or 
it may be present in either a greater or a less concentration 
in the urinary membrane than in the blood. Just what will 
happen is dependent upon the nature of the dissolved substance 
and the physical and chemical composition of the blood and the 
urinary membrane at the time. Of greatest importance are 
such facts as the presence and absence of lipoids, the character 
of the colloids concerned, and the state of these colloids as 
determined by the presence of acids, alkalies, salts, or various 
non-electrolytes. In other words, the laws of partition again 
come into play. These differences in the distribution of a dis- 
solved substance between the blood and the urinary membrane 
are rendered strikingly apparent when dyes are used as the 
dissolved substances. 

But this distribution of a dissolved substance between the 
blood and the urinary membrane represents in the end only a 
static affair, and the secretion of dissolved substances in the 
urine is a dynamic one. It requires no special comment to see 
now why only through the continuous secretion of water from the 
kidney can a continuous separation of dissolved substance from the 
urinary membrane (secretion) be rendered possible. The presence 
of water in Bowman's capsule and in the uriniferous tubules intro- 
duces the third phase into our secretory system and breaks down 
continuously the equilibrium that is trying to become established 
between the dissolved substances in the blood and the dissolved sub- 
stances in the urinary membrane. 

The attempt to establish an equilibrium between the dis- 
solved substances in the urinary membrane and the dissolved 

1 The word soluble is used in these paragraphs in its broadest sense, so as 
to include even the pseudo-soluble (colloid) substances. 



370 



(EDEMA AND NEPHRITIS 



substances in the urine (originally only water) as it passes down 
the uriniferous tubules makes for a diffusion of dissolved sub- 
stances out of the urinary membrane, and so all the time that 
w r ater is being secreted by the kidney, tends to destroy the equi- 
librium, which is trying to become established between the dis- 
solved substances in the blood and the dissolved substances 
in the urinary membrane. When now w r e recall the physico- 
chemical fact that when any dissolved substance is offered simul- 
taneously to a liquid colloid, a solid colloid, and water (as is the case 
in the kidney), an unequal distribution of the dissolved substance 
between the three phases is the rule, then we will have no dif- 
ficulty in understanding why a difference in quantitative com- 
position between the blood, kidney tissue, and urine, so far as 
dissolved substances are concerned, is also the rule. Wherefore 
a ''selective" secretion is to be expected rather than to be won- 
dered at. 

Our considerations also indicate how, corresponding with 
differences in the colloid constitution of the different parts of the 
urinary tubule, these may show qualitative and quantitative 
differences in the way in which they secrete the various constit- 
uents of the blood. . Physiologists have long believed that such 
differences in function exist. 

It is also a matter of indifference to us as to where it is held 
that the water of the urine is secreted. If this be in the glome- 
ruli, as generally maintained (but not as yet experimentally 
proved), then we can imagine the water to leach out the various 
urinary constituents from the secreting membrane as it passes down 
the uriniferous tubule on its way to the pelvis of the kidney. If 
w r ater is secreted by several or all portions of the uriniferous 
tubule, the problem remains, from our point of view, essentially 
the same. 

Our theory also permits of the reabsorption of water, or of 
dissolved substances, or of both from the fluid passing down the 
uriniferous tubules as postulated by some observers. It cannot, 
of course, as yet be accepted that such a reabsorption does occur 
physiologically. That a reabsorption can occur is undoubtedly 
correct, but the experiments made to furnish evidence for such a 
belief unquestionably interfere with the normal function of the 
kidney. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 371 



11. A Second Model Illustrating Some Phases of Kidney 
Secretion 

For those interested in the matter, we may now return to a 
further discussion of the construction of physico-chemical systems 
which in their behavior mimic what happens in " living " 
biological secretory systems. To this end I have recently made 
use of a principle first discovered by Thomas Graham and of 
another emphasized chiefly by Richard Maly which, in con- 
nection with various observations of my own, make easy the 
laboratory demonstration of certain physiological and patho- 
logical facts regarding secretion in general, or urinary secretion in 
particular, which are ordinarily assumed to be inexplicable in 
simple physico-chemical terms, and, for the understanding of 
which, the vague, " vital " forces of protoplasm are too often 
called into action. 1 It is still a source of wonder to many bio- 
logical workers that a neutral or alkaline kidney parenchyma can 
be the mother of an acid urine; that the kidney assiduously " pro- 
tects " the living animal from being overwhelmed by acid or alkali; 
that various constituents characteristic of urine are found here in a 
different proportion from that of these same substances in the 
kidney parenchyma or in the blood flowing through this; etc. 
As the following shows, the entire biological fabric is readily repro- 
ducible from the simple strands furnished by the concepts of 
modern colloid chemistry. 

§1 

Thomas Graham 2 showed many years ago that when any 
readily hydrolyzable salt, like ferric chlorid, is put into a sac (like 
parchment) which is permeable to molecularly dispersed sub- 
stances (crystalloids), but impermeable to more grossly dispersed 
ones (colloids) and the whole is then hung into water, as shown in 
Fig. 118 (is subjected, in other words, to dialysis), the following 
changes occur: Because of the hydrolysis of the ferric chlorid, ferric 
hydroxid and hydrochloric acid are produced. Since the hydro- 
chloric acid is highly diffusible, it at once begins to escape through 

1 Martin H. Fischer: Jour. Lab. and Clin. Med., 5, 207 (1920). 

2 Thomas Graham: Quoted by Wolfgang Ostwald in Handbook of 
Colloid Chemistry, translated by Martin H. Fischer, 2d Ed., 233, Phila- 
delphia (1919). 



372 



(EDEMA AND NEPHRITIS 



the parchment membrane into the surrounding bath of water. 
Ferric hydroxid remains behind. 

The example here chosen is, of course, not an isolated one. It 
is characteristic in general of all the hydroiyzable salts. This 




Figure 118. 



dialysis method was, in fact, used by Graham for the production 
of many different kinds of non-diffusing "colloids " from the pure 
solutions of what were originally only molecularly dispersed and 
highly diffusible salts. 

A quantitative study of the chemical changes which occur in 
the experiment just described has been made by S. E. Linder and 
H. Picton. 1 This shows that the proportion of iron to hydro- 
1 S. E. Linder and H. Picton: Trans. Chem. Soc, 1909 (1905). 



ABSORPTION, SECRETION— COMPLEX ORGANISM 373 



chloric acid steadily increases within the diffusion thimble while it 
as steadily decreases in the water surrounding the thimble. In 
other words, the amount of ferric hydroxid increases progressively 
within the thimble, while the amount of the hydrochloric acid 
increases without. Iron finally ceases to come out from the inter- 
nal liquid. The reason for all this is found in the fact that the 
originally diffusible iron chlorid gradually goes over into a " col- 
loid " iron hydroxid which can no longer pass through the parch- 
ment membrane since it contains no holes large enough to let such 
super-molecular aggregates through. 

A quantitative study of the physical changes of the thimble 
contents in this dialysis experiment has been made by N. Sahl- 
bom. 1 By subjecting the solution of iron contained within the 
diffusion capsule to " capillary analysis " (in which are utilized the 
principles first discovered by John Uri Lloyd 2 and Friedrich 
Goppelsroeder 3 ) the gradual repla cement of the originally highly 
diffusible iron salt by a non-diffusing colloid one can easily be made 
a matter of ocular demonstration. If strips of filter paper are 
simply dipped into the liquid contents of the diffusion thimble on 
successive days, it is found that, on the first day, both the dis- 
persion medium (water) and the dispersed substance (iron salt) 
ascend the paper as shown in the first strip of Fig. 119. However, 
as the change in the thimble contents progresses, the dispersion 
medium is still found to ascend the paper, but there is a progressive 
reduction in the height to which the iron salt will go. In the final 
stages of the exper ment (after the dialysis has been continued for 
several days) the colloid ferric hydroxid scarcely diffuses at all, 
coming to rest almost immediately above the surface of the liquid 
into which the filter paper has been dipped, as shown in the right 
hand strip in Fig. 119. 

This whole experiment may be readily repeated for demon- 
stration purposes in the following fashion. An ordinary parch- 
ment paper diffusion thimble (one capable of holding 20 cc. or 
more) is filled to near its top with am/5 (about 5 per cent) solution 
of ferric chlorid (FeCl3 • 6H 2 0). The thimble with its contents is 

1 N. Sahlbom: Kolloidchem. Beihefte, 2, 79 (1910). 

2 John Uri Lloyd: Proc. Am. Pharmaceut. Assoc., 32, 410 (1884), where 
references to even earlier studies by him on "capillary analysis" may be 
found. 

3 Friedrich Goppelsroeder: Capillaranalyse, Basel (1901), where 
references to his earlier papers may be found. 



374 



OEDEMA AND NEPHRITIS 



then suspended in a larger bottle or Erlenmeyer flask as shown in 
Fig. 118, enough distilled water being poured into the container 

to bring its level up to the level of 
the ferric chlorid in the thimble. 
The distilled water must, naturally, 
be changed two or more times daily 
in order to get rid of the products 
of diffusion. 

The acid nature of the wash 
water is readily demonstrated by 
adding to it some indicator like 
methyl red. The presence of iron 
in it is betrayed by the slightly 
yellowish tinge observable in the 
first few hours or days of the experi- 
ment. If desired, the iron may be 
demonstrated quantitatively by 
adding to a given amount of wash 
water a solution of potassium ferro- 
cyanid. While originally a heavy 
precipitate is obtained as shown in 
Figure 119. the left hand tube of Fig. 120, it 

becomes progressively less until, at 
the end of four or five days, it disappears entirely. This is shown 
in the tube marked 5 in Fig. 120. If, now, when the loss of iron 
has dropped to this zero point, some hydrochloric acid is added 
to the contents of the diffusion thimble, the iron reappears in the 
surrounding water as shown in the right hand tube of Fig. 120. 

The change to the electronegative ferric hydroxid within the 
diffusion thimble may be followed by dipping strips of filter paper 
into the diffusion thimble from day to day and noticing the height 
to which the color ascends. In the first days the iron salt and the 
water rise together to a great height, but later (after four to ten 
days) the water still rises, but the now colloid iron comes to rest 
just over the surface of the liquid as shown in Fig. 119. 

It is important to point out next the analogies which exist 
between this simple experiment and certain facts of kidney func- 
tion. If we will call the contents of the diffusion capsule " kidney 
parenchyma" and the water surrounding the capsule " urine " 
—the entirely secondary importance of the diffusion capsule will 




ABSORPTION, SECRETION— COMPLEX ORGANISM 375 



be pointed out later — the following facts will at once become ap- 
parent. 

It is obvious, first of all, that there is always derived from the 
thimble contents a secretion more acid than the medium from 
which it comes, just as there escapes from the kidney a urine more 
acid than the tissues themselves. In the later stages of the diffu- 
sion experiment an acid secretion is obtained not merely from a 



III 


1 


1 


a 




a 




3 

















Figure 120. 



medium which is less acid, but from one which is actually " alka- 
line." The fact that the ferric hydroxid no longer ascends the 
filter paper means just this. It is, in other words, an electroneg- 
ative (alkaline) colloid. But the analogy to kidney physiology 
and pathology goes further. Ferric hydroxid, except in low con- 
centrations, is a definitely " gelatinous " colloid. Even in the con- 
centrations employed in these experiments it is not an ordinary 
hydrophobic colloid, but shows distinctly hydrophilic properties. 
As the argument of the preceding pages has proved, it is this 
hydrophilic type of colloid which constitutes the bulk of what is 



376 



(EDEMA AND NEPHRITIS 



termed protoplasm. The "alkaline " ferric hydroxid is, in other 
words, the analog of the normal " electronegative " colloids 
which make up kidney parenchyma. 

It is in the later stages of Graham's experiment when an acid 
secretion of molecularly dispersed substances containing no iron 
is being derived from a hydrophilic colloidally dispersed matrix 
that we have the parallel of what happens in kidney and urine 
under physiological conditions. The hydrated ferric hydroxid in 
the presence of traces of salts does not " dissolve " in water (just 
as no albumin dissolves out of the kidney to appear in normal 
urine). But if the acid content of the ferric hydroxid is slightly 
increased, the colloid " dissolves " more easily, shows increased 
diffusibility and becomes readily miscible with water. In the case 
of Graham's experiment the iron now diffuses through the parch- 
ment capsule and " appears in the urine." This is analogous to 
what happens in the kidney under pathological circumstances, as 
in nephritis. 1 Under the influence of the abnormal production 
or accumulation of acids (or of similarly acting substances like 
alkalies, amins, pyridin and urea) in the kidney parenchyma, this 
not only swells, but shows an increased tendency 7 - to diffuse and an 
increased miscibility with water, and this explains why the material 
of the colloid matrix, in other words, albumin, begins to appear 
in the liquid which bathes the parenchyma. The urine, in other 
words, from which under normal circumstances albumin is absent, 
now contains such. Accompanying such change, however, there 
is an increase in the titration or hydrogen-ion acidity of the urine 
expressive of the increased acid content of the kidney parenchyma. 
In similar fashion, in Graham's experiment there is a loss of iron 
during the first hours and while the acid content of thimble mix- 
ture and external fluid is high, to become less and less as the 
more rapid loss of acid allows the iron to change to a hydroxid 
and a non-diffusible form. The renewed addition of acid to the 
colloid iron hydroxid within the thimble again increases the 
solubility and diffusibility of the iron and at once this manifests 
itself by a renewed appearance of this metal in the wash water 
about the diffusion thimble. 

The diffusion capsule, it must be clearly kept in mind, is of 
entirely secondary importance. Even if it were absent, the same 
results would be obtained, for the parchment thimble only man- 

1 See page 504. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 377 



ages in mechanical fashion to keep together the iron solution. 
Separation through diffusion is the same whether such diffusion is 
" free " or partially hampered through a colloid membrane. 

In the case of a normal kidney the parenchyma itself (the 
protoplasm of the cells) behaves like the parchment thimble. In 
nephritis such colloid structures are destroyed and the kidney 
mixes with the urine just as the non-colloid iron salt would mix 
with the water, were no parchment thimble present. 

§2 

In order to show that an entirely analogous behavior is observ- 
able if a protein is used instead of an iron salt, the following experi- 
ment with gelatin was devised. Gelatin shows, like other proteins 
an increasing tendency to liquefy or " dissolve " (an increased 
degree of dispersion and an increased tendency to diffuse) in the 
presence of sodium phosphate as the acid or alkaline content of the 
phosphate mixture is increased from a given low point. 1 The 
Erlenmeyer flasks of Fig. 121 contained the following gelatin- 
phosphate-water mixtures : 

1. 50 cc. 2% gelatin+3 cc. m/1 NaH 2 P0 4 +4 cc. n/1 H 3 P0 4 

+43cc. H 2 0, 

2. 50 cc. 2% gelatin+3 cc. m/1 NaH 2 P0 4 +3 cc. n/1 H 3 P0 4 

+44 cc. H 2 0. 

3. 50 cc. 2% gelatin+3 cc. m/1 NaH 2 P0 4 +2 cc. n/1 H 3 P0 4 

+45 cc. H 2 0. 

As shown in previous observations on this gelatin, these 
mixtures are just liquid to decidedly liquid at 21° C, a fact readily 
manifest in the photograph. These liquid mixtures were poured 
into ordinary parchment diffusion capsules and dialyzed against 
distilled water for a number of days. On the fourth day of the 
dialysis the gelatin in the diffusion thimble of 3 had become semi- 
solid, while that in the remaining thimbles was still liquid. On the 
fifth day the gelatin from the third mixture was solid, that in the 

1 See page 596, also Martin H.Fischer: Science, 46, 189 (1917); Mar- 
tin H. Fischer and Ward D. Coffman: Jour. Am. Chem. Soc, 40, 303 
(1918). 



ABSORPTION, SECRETION—COMPLEX ORGANISM 379 



second semi-solid, while that in the first was still liquid. At the 
end of ten days all were solid. 1 

To understand what has happened it is only necessary to call to 
mind Richard Maly's 2 classical observations on diffusion. In 
order to get a physico-chemical counterpart of the production of a 
secretion (like gastric juice or urine) more acid than its source 
(the glandular parenchyma or the blood) he studied the separa- 
tion which occurs when free diffusion or diffusion through a parch- 
ment membrane is permitted a mixture of acid with an acid salt 
or one of an acid salt with a neutral salt, etc. Generally speaking, 
the more acid constituents of such a mixture leave it first, leaving 
behind the more neutral compounds. It is this principle which is 
utilized in the experiment described above. From a phosphate 
mixture containing phosphoric acid, the phosphoric acid diffuses 
out sooner than the acid phosphate ; while from the acid phosphate 
itself an acid fraction diffuses out leaving behind disodium phos- 
phate. As this occurs, the previously liquid gelatin becomes more 
and more viscid until, as " neutrality " is approached, the mixture 
becomes solid. 

The experiment shows in reverse order the state which char- 
acterizes the kidney in nephritis and normally. As will be shown 
later, 3 albuminuria represents a " solution " of the previously 
insoluble kidney and is brought about through an accumulation in 
the kidney parenchyma of materials like acids (alkalies, amins, 
pyridin or urea). The continuance of the kidney in its normal 
solid state is dependent upon the maintenance in this structure of 
a reaction mose nearly neutral. In the experiment described 
above this " normal " state of the kidney is represented by the solid 
gelatin in the diffusion capsule at the end of the experiment; the 
nephritic state, by the liquid gelatin readily miscible with water 
with which the experiment was started. While the urine of the 
carnivora is for most of each day and normally more acid than the 
kidney parenchyma or the blood, this acidity is greatly increased 
under the pathological circumstances which are associated with 

1 To reduce liability to infection with liquefying organisms it is well to 
make up the gelatin mixtures in sterile form, to soak the diffusion capsules 
in boiling distilled water before use, and to keep the diffusion flasks stoppered 
with sterile cotton plugs. 

2 Richard Maly: Zeitschr. f. Physiol. Chem., 1, 174 (1877). 

3 See page 507, also Martin H. Fischer: (Edema and Nephritis, 2d Ed., 
433, New York (1915), where references to the earlier papers may be found. 



380 



(EDEMA AND NEPHRITIS 



" nephritis.'' These facts, too, may be readily observed in the 
described experiment. 

The more acid nature of the " secretion " in the experiment 
described above as compared with that of the " parenchyma " 
(the gelatin mixture) may be observed at any stage of the diffusion 
by adding some indicator like methyl red or Htmus to the capsule 
contents and to the wash water surrounding the capsule. While 
I hold that there are serious objections to be raised against the 
application of indicator methods to definitely colloid S3^stems and 
to the interpretations which are ordinarily made of such findings 1 
it is nevertheless true that the acidity of the wash water gradually 
falls. While originally, for example, methyl red is turned violently 
red, this indicator shows only a reddish-brown color when diffusion 
has been allowed to progress for several days. 

12. A Third Model Illustrating Some Phases of Kidney 

Secretion 2 

We purpose returning in these paragraphs to that half of the 
secretory process which has to do with the mechanism by which a 
glandular parenchyma separates water from the blood and thus 
fathers a secretion. 

§i 

If we ignore the entirely purposeless efforts to explain such 
separation on a " physiological" basis — which amount in essence 
to nothing more than the statement that a cell secretes because it 
secretes and that it fails to secrete because it can not — then the 
attempts to account for what is observed may be divided into two 
classes. The first of these is the filtration theory originally put 
forth in purely speculative form by Bowman and later upon an 
experimental basis by Carl Ludwig and his followers. The 
second is properly not a theory at all, but really only a critique 
of the Bowman- Ludwig concept by R. Heidenhain and his 
successors, who, on the basis of various physiological observations 
(in which the questions of the secretion of water and the secretion 

x See pages 765 and 775. Also Martin H. Fischer: Science, 49,615 
(1919); Chem. Engineer, 27, 271 (1919). 

2 Martin H.Fischer and George D, McLaughlin: Jour. Lab. and 
Clin. Med., 5, 352 (1920). 



ABSORPTION, SECRETION— COMPLEX ORGANISM 381 

of various dissolved substances are hopelessly confused) negate 
the adequacy of the filtration hypothesis. A good illustration of 
the modern situation is furnished by the work previously cited of 
T. G. Brodie and his co-workers, 1 who, from their experiments on 
urinary secretion, came to the conclusion that the secretion of 
water by such an organ as the kidney is paralleled by a consump- 
tion of oxygen. At times there was also an increased carbon dioxid 
production. In plainer terms, such a parallelism means that in 
secreting water the kidney does work, that this work calls for a 
consumption of energy, and that the greater the amount of work 
thus done, the greater the consumption of energy. While we have 
ourselves supported such a view, 2 recent studies 3 on the structure 
of colloid systems and the analogy existing between these and pro- 
toplasm has made us look into the whole problem anew. The 
experimental findings of Brodie and his co-workers have, moreover, 
been drawn in question by the observations of other authors, 
notably those of J. Barcroft and H. Straub, 4 who noted an even 
twentyfold increase in water output by the kidney, under the 
influence of injections of various salt solutions, with no appreciable 
increase in oxygen consumption. As must be apparent, the two 
observations are mutually exclusive for were they both correct, 
it would compel the conclusion tha,t to secrete water the kidney 
must sometimes do work and sometimes not. Is there a less in- 
consistent way out? 

In our opinion there is, provided we will stop confusing the two 
elements of the secretion of water and the secretion of dissolved 
substances, and bear in mind the conditions experimentally found 
necessary for every increase or decrease in the secretion of these 
two materials and the significance of such conditions in the body 
of the living animal from a colloid-chemical point of view. 

Our previous studies have shown that the conditions making 
for the absorption of water by the colloid-chemical mass which we 
term a living animal, are the opposite of those which make for the 

1 J. Barcroft and T. G. Brodie. Journal of Physiol., 32, 18 (1904); 
ibid., 33, 52 (1905);. T. G. Brodie and W. C. Cullis: Journal of Physiol., 
34,224 (1906); T. G. Brodie: Harvey Lectures, Phila. (1909) ; A.R.Cushny: 
Secretion of Urine, 34, 35, London (1917). 

2 See the first and second editions of this volume. 

3 Marian O. Hooker and Martin H. Fischer: Chem. Engineer, 27, 
155, 223, 253 (1919); Martin H. Fischer: Chem. Engineer, 27, 184, 271 
(1919). 

4 J. Barcroft and H. Straub: Journal of Physiol., 41, 145 (1911). 



382 



(EDEMA AND NEPHRITIS 



secretion of this same substance. Thus water is absorbed only 
as the capacity of the body colloids for holding water is increased 
by any of various circumstances, while a separation or secretion 
of water follows as these conditions are reversed. Water is there- 
fore best absorbed in those portions of the alimentary tract (the 
large intestine) which are bathed by the most venous blood (that 
richest in carbonic or other acids) while no such absorption occurs 
in the stomach during the "periods of digestion" when this viscus 
is supplied with highly arterialized blood. A secretion of water, 
after its absorption into the venous blood, becomes possible 
as soon as the acid content of this venous blood (carbonic acid 
under normal circumstances or other acids in states of disease) is 
diminished on passing through the lungs. At this point water 
becomes "free" and may be lost through any secretory organ. 
A first place of loss is in the lung itself, while the other places of 
loss of general importance are represented by the kidney and the 
sweat glands of the skin. To make possible a secretion of water, 
the following conditions must, therefore, be satisfied: (1) "free" 
water must be brought to the secreting parenchyma, (2) the 
blood carrying such free water must contain a sufficiently low 
concentration of various acids (and a sufficiently high con- 
centration of oxygen) and (3) if the secretion of water is to 
cost the kidney or other secreting gland no work the secreting 
parenchyma must be " permeable " to the free water and not to 
the combined. 

The previous pages have shown how the experimental data of 
other authors, as well as our own all support the first two of these 
conclusions. A water-starved animal is incapable of any secre- 
tion; and the injection of any amount of water in combined form 
(as whole blood, blood plasma or any proper hydrophilic colloid) 
will not increase any secretion by a drop. Secretion increases and 
is proportional to the amount of "free" water furnished the secre- 
ting organ (in other words, the amount available above that neces- 
sary for saturation of the colloids). When secretion-promoting 
substances like saline diuretics or materials of the type of caffeine 
and digitalis are used, the mechanism still remains in essence the 
same. In the first instance, the administered salts dehydrate the 
body colloids generally, and thus make available free water for 
secretion, while, in the second instance, they increase cardiac and 
respiratory efficiency, and by thus increasing the circulation 



ABSORPTION, SECRETION— COMPLEX ORGANISM 383 



through the tissues, decrease their content of carbonic and other 
acids, thus again making for the appearance of the free water 
necessary for secretion. 

These ideas may be applied to such experiments as those of 
Brodie and his followers, and Barcroft and Straub. While 
insisting upon the general parallelism between amount of oxygen 
consumed and water secreted a study of the individual protocols 
and foot-notes of even the first named of these authors indicates 
that he himself failed to discover such parallelism whenever a 
diuretic salt was administered; and this is the rule in all of Bar- 
croft and Straub's findings. We would, in our own terms, say 
that these facts compel the conclusion that the secretion of "free" 
water does not cost a kidney or other secreting organ any work. 
This conclusion is the logical one demanded by the colloid-chem- 
ical theories of absorption and secretion for which we have so 
long stood, but because such apparently finite experiments and 
deductions as those of Brodie stood against us we, too, insisted 
that water secretion represented an "active" process, 1 and thus 
failed to find in filtration and the "microcapillary" structure of 
the colloids (as illustrated in our first urinary secretion model 2 ) 
an explanation of all the phenomena observed in a living animal. 
// the secretion of water is essentially a filtration process, simple 
hydrated colloids of proper composition ought to behave like kidney 
parenchyma. The following experiments show that they do. 

§2 

We chose for particular study the system, hydrated sodium 
stearate. For filtration purposes this was cast into cylindrical 
cups measuring in the moist condition 7.2 cm. transversely by 
5.2 cm. high, with walls 1 cm. thick. The cups were made by 
supporting one calibrated beaker (of 120 cc. capacity) within a 
second (of 350 cc. capacity) and filling the intervening space with a 
hot sodium stearate solution. After the material had "set" by 
being cooled to room temperature, the soap model was removed 
from the mold and set up for experimental purposes as indicated 
in Fig. 122 except that the whole was covered so as to prevent un- 

1 Martin H. Fischer: (Edema and Nephritis, 2d Ed., 314, New York 
(1915). 

2 See page 327. 



384 (EDEMA AND NEPHRITIS 



due evaporation. In the experiments to be described, the filtra- 
tion properties of the cups were then tested by filling them with 80 
cc. of the solution to be filtered. The filtration pressure (the 
hydrostatic pressure) represented by this volume of fluid is 5 cm. 




Figure 122. 



Water filters through such a soap cup in a fashion remarkably 
analogous to that observed in the various secreting organs of the body. 

1. We tested out first the effects of the concentration of the 
hydrated sodium stearate system upon the filtration of water 
through it. The amounts of water which will pass through a 
sodium stearate cup of different concentrations under the cir- 
cumstances described for these experiments are indicated in 
Table XCVI. 

These experiments show that the ease with which water filters 
through a hydrated sodium stearate decreases with every increase 
in the concentration of the colloid membrane. The filtration 
capacities of the different soap cups are so strikingly different that 
they are readily apparent to the naked eye as shown in Fig. 123, 
which is a photograph of this experiment at its end. 

2. It was our next purpose to demonstrate the gross differences 
existent between the rate at which "free" water will filter through 



ABSORPTION, SECRETION— COMPLEX ORGANISM 385 



TABLE XCVI 

Amount of Water in cc. Which Filters through Sodium Stearate 
Cups of Different Concentrations 



Hours allowed for filtration. 


Concentration of Sodium Stearate cup. 


















m/2 


2/5 m 


3/10 m 


2/10 m 


m/10 


m/20 


2 


45 














3 


27 


4 




1 


2 


1 


1 


6 


34 


5 




1 


3 


3 


2 


8 


42 


6 




2 


3 


4 


2 


10 


46* 


8 




3 


5 


5 


4 


14 


62 


24 


15 


3 


10 


11 


12 


36 


96 


Neutralization 


value in cc. n/10 














H2SO4 of whole filtrate 


.1 


.5 


.6 


.6 


1.2 


1.4 


Neutralization 


value per cc. of 














filtrate 




.033 


.050 


.054 


.050 


.033 


.014 



* 25 cc. more H2O added to this cup. 



TABLE XCVII 

Amount of Water in cc. Which Filters through m/10 Sodium Stearate 
Cups When "Free" or "Combined" with Hydratable Colloid 



1 - 




Composition of liquid being filtered. 


Hours allowed for 






filtration. 










H2O 




m/1 Sodium Oleate 




30 


2 





1 


15 


6 





2 


15 


9 





3 


15 


15 





4 


15 


19 





5 


15 


23 





20 


00 


30 






TABLE XCVIII 



Amount of Water in cc. Which Filters through m/10 Sodium Stearate 
Cups from Pure Water or Solutions of Sodium Chlorid of Dif- 
ferent Concentrations 



Hours allowed for 


Composition of liquid being filtered. 


filtration. 


H2O 


m/8 NaCl 


m/4 NaCI 


m/1 NaCl 


4 
7 


10 
16 


13 
19 


15 
22 


20 
27 



ABSORPTION, SECRETION— COMPLEX ORGANISM 387 

such a colloid cup and combined water as represented by a liquid 
colloid which in its physical constitution may be compared with 
blood. To this end we compared the filtration of water with that 
of a molar ''solution" of sodium oleate. Since in the previous 
series of experiments m/10 sodium stearate cups had yielded a 
good average filtration rate we chose these for this experiment and 
the subsequent ones. 

This experiment shows that water when combined with a 
hydrophilic colloid fails to come through a hydrated soap just as 
urine fails to come from blood when this contains no "free" water. 
That it is nothing specific about the sodium oleate which makes 
the filtration of water impossible, but merely the fact that the 
water is bound to the sodium oleate, is proved by the fact that 
mere dilution of the sodium oleate, sufficient to guarantee the 
presence of free water, at once allows some liquid to filter through. 
Its amount in no instance, however, equals that when pure water 
is used. 

3. These colloid soap cups may be used to illustrate even the 
biological action of the various salines in increasing secretion. 
The saline diuretics owe their effects 1 to a dehydrating action upon 
the hydrophilic (protein) colloids of the body in general and upon 
those of the kidney in particular. By dehydrating the proteins 
of the body in general, they furnish "free" water for the kidney to 
secrete, while through such action upon the kidney specifically, 
they not only exhibit this function, but through it, obviously, the 
diameter of the capillaries must be increased which must be exist- 
ent in the glandular parenchyma if mere filtration is presumed 
to be the mechanism by which free water is squeezed off from the 
blood. 

The effects of the salines are different both as to their concen- 
tration and their kind. Table XCVIII illustrates upon colloid 
soap how the "diuretic" effect of any salt is increased with every 
increase in its concentration. 

The results of this experiment at the end of 7 hours are shown 
in Fig. 124. 

4. Table XCIX illustrates the difference in effects when equally 
concentrated (equimolar) solutions of salts possessed of a common 
acid but different basic radicals are filtered through a series of 
cups. 

1 See page 339. 



ABSORPTION, SECRETION — COMPLEX ORGANISM 389 



TABLE XCIX 

Amount of Water in cc. Which Filters through m/10 Sodium Stearate 
Cups from Equimolar Solutions of Different Salts 



Composition of liquid being filtered. 



for filtration. 


H2O 


m/8 NH4CI 


m/8 NaCl 


m/8 MgCl 2 


m/8 CaCl 2 


:30 


1 


3 


3 


3 


4 


1:15 


2 


6 


8 


10 


10 


2: 15 


6 


9 


14 


20 


23 


3:15 


9 


12 


20 


29 


35 


4:30 


15 


14 


27 


40 


50 


5:30 


19 


16 


33 


52 


64 


6:30 


23 


17 


38 


58 


70 


7:50 


30 


18 


42 


62 


72 



The results of this experiment at its end are shown in the photo- 
graph of Fig. 125. 

It is to be noted that the ammonium chlorid leads to a decrease 
in secretion as compared with the effects of pure water. On the 
other hand, magnesium and calcium chlorid are more powerful 
"diuretics" than sodium chlorid. We return to a discussion of 
these findings later. 

TABLE C 



Amount of Water in cc. Which Filters through m/10 Sodium Stearate 
Cups from Equimolar Solutions of Different Salts 







Composition of liquid being filtered. 




Hours allowed 














for filtration. 
















H2O 


m/8 


m '8 


m/8 


m/8 


m/8 




NaCl 


NaaSOj 


Na acetate 


Na 2 HP() 4 


Na citrate 


1 


1 


1 


2 


1 


1 


1 


2:30 


3 


5 


4 


2 


3 


3 


3:30 


5 


7 


6 


4 


4 


5 


5:30 


8 


12 


10 


7 


7 


10 


6:30 


11 


14 


12 


9 


8 


14 


7:30 


12(?) 


16 


13 


11 


9 


17 


24:10 


37(?) 


37 


35 


31 


30 


cup broken 


Neutralization 














value in cc. n/10 


.14 


.7 


.7 


.6 


.6 




H2SO4 of whole 














filtrate 















We tried next the effects upon filtration of equally concentrated 
(either equinormal or equimolar) solutions of salts containing a 
common basic radical with different acid radicals. Table C gives 



ABSORPTION, SECRETION— COMPLEX ORGANISM 391 



TABLE CI 



Amount of Water in cc. Which Filters through m/10 Sodium Stearate 
Cups from Equinormal Solutions of Different Salts 







Composition of liquid being filtered. 




TTrmrc oil owprJ 














for filtration. 
















H2O 


m/8 


m/16 


m/8 


m/24 


m/24 




NaCl 


Na 2 S04 


Na acetate 


NaHP04 


Na citrate 


1 


1 


2 


2 


1 


1 




2 


2 


4 


3 


1 


2 


2 


3 


4 • 


6 


4 


4 


2 


2 


4 


5 


=• 7 ' , 


6 


4 


4 


4 


5 


6 


9 


7 


5 


5 


5 


6 


8 


11 


8 


7 


7 


7 


7 


9 


13 


9 


8 


7 


8 


22 


30 


32 


27 


28 


24 


28 


Neutralization 














value in cc. n/10 


1.3 


.7 


.8 


.7 


.8 


.5 


H2SO1 of whole 














filtrate 















the results when equimolar solutions are used, while Table CI 
and Fig. 126 give the findings when equinormal solutions are 
employed. It will be observed that within the limits of experi- 
mental error there is no change in either case in amount of water 
secreted as compared with the effects of sodium chlorid. In other 
words, the greater diuretic action of the acetates, citrates, phos- 
phates and sulphates observed in living animals as compared with 
the diuretic action of equally concentrated chlorids, bromids, or 
iodids does not appear in these filtration experiments with soaps. 
To the discussion of this finding we also return below. 

6. There exists a variable in all the described experiments which 
may be made a constant when it is so desired. In the simple 
arrangement described above, the filtration pressure falls as the 
amount of liquid which passes through the cup increases. Since, 
besides, the filtrate is not removed as formed, more and more 
accumulates about the cup and thus reduces the surface available 
for filtration. Both objections may be overcome by utilizing the 
filtration arrangement with constant level shown in Fig. 127. 

In Fig. 127, b represents in section a sodium stearate cup sup- 
ported upon a coarse, galvanized iron screen held in a ring stand. 
In proper position above the cup is supported the inverted 100 cc. 
graduate a. At the beginning of the experiment the cup b rnd the 
graduate a are filled with the liquid to be filtered, the filled gradu- 



392 



(EDEMA AND NEPHRITIS 




ate being inverted and placed in position as indicated in the figure. 
The filtration pressure is obviously determined by the height of 
the liquid standing in b. As liquid filters through the cup and its 



ABSORPTION, SECRETION— COMPLEX ORGANISM 393 

level falls in b, air enters the graduate, allowing the liquid column 
in a to fall sufficiently to restore the old level in b. In this way the 
nitration pressure available in b is kept constant. 
Any liquid which filters through b is caught by the 
funnel c and collected in the graduate d from which 
direct readings as to quantity of filtrate may be 
made. 

§3 

1. The model described above may also be used 
to demonstrate various facts regarding the secretion 
of dissolved substances. A first point again covers 
the matter of how a secretion more alkaline may 
be derived from a less alkaline or even neutral 
source (parenchyma or blood) . If phenolphthalein 
is added to the solution being filtered, is applied 
to the soap of the cup, and is added to the secretion 
escaping from the soap cup, in such an experi- 
mental series as indicated in Table XCVIII 
(where water and sodium chlorid solutions of 
different concentrations are being filtered) the fol- 
lowing facts may be observed. The original salt 
solutions leave phenolphthalein uncolored; so also 
do the sodium stearate cups; in the case of the 
filtrates, however, that from pure water turns the 
phenolphthalein brilliantly red. The same is true, 
though in decreasing intensity, as we examine the 
" secretions " from the cups containing increasingly Figure 127. 
stronger sodium chlorid solutions. The filtrate 
from the sodium chlorid of highest concentration may leave the 
phenolphthalein practically uncolored. 

Expressed in ordinary terms, alkaline secretions are here being 
derived from parenchymas or blood which are by themselves neu- 
tral or even acid. There is, however, nothing mysterious in the 
observed facts if a previous study on the composition of the lyo- 
philic colloids and of the behavior of the colloid soaps toward 
indicators is kept in mind. 1 Distilled water and aqueous solu- 
tions of neutral salts are of course not expected to color phenol- 

1 Martin H. Fischer: Science, 48, 143 (1918); ibid., 49, 615 (1919); 
Chem. Engineer, 27, 184, 271 (1919). See also page 775. 





394 



OEDEMA AND NEPHRITIS 



phthalein. The solid soap cups are essentially solutions of water 
in sodium stearate and such hydrated soap colloids also leave 
phenolphthalein uncolored. But upon diluting such a colloid, 
the soap dissolves in the water and such solutions of soap in water 
do color phenolphthalein. Hence the secretion which has passed 
through the solid sodium stearate is "alkaline" in reaction. This 
solubility of the soap in water decreases, however, as neutral salt 
is added to the water, hence less soap dissolves and hence less 
reaction to the phenolphthalein. 

The biological significance of these findings (aside from the light 
which they throw upon the mechanism by which secretions more 
or less acid or alkaline may be obtained from allegedly more 
neutral sources) is of course great. In the terms of the pure physi- 
cal chemists, the dilute soap solutions, as represented by the 
filtrates, are alkaline because, after hydrolysis of the dissolved 
soap, there is present an excess of hydroxjd ions. By the same 
reasoning the soap cups show no reaction to phenolphthalein 
because these are too "concentrated soap solutions." Even if we 
allow the correctness of such deductions — we are ourselves of the 
opinion that indicator methods are largely inapplicable here 1 — the 
necessary additional conclusions are still of small comfort to orthodox 
physiology. From a colloid point of view protoplasm behaves like 
the soap cup and blood and lymph like a concentrated liquid col- 
loid of the type of sodium oleate. By the indicator methods these 
show no ions. Are the physical chemists who believe in the un- 
restricted applicability of the laws of dilute solutions to living 
cells going to admit that solid protoplasm and blood and lymph 
under normal circumstances contain practically no ions, and that 
they have in consequence ascribed to the theories of dilute solution, 
electrolytic dissociation, etc., an importance which they in no sense 
can exercise in normal living tissues? We believe, as a matter of 
fact, that normal uninjured protoplasm is, from a physical point 
of view, electrically neutral and that there are in it under normal 
circumstances as few or less electrically charged atoms and groups 
of atoms as in pure water or alcohol or ether or a dry crystal hold- 
ing water of crystallization. Protoplasm is, in other words, a 
"solution" of water in hydrophilic colloid and this is a system to 
which the physico-chemical laws covering the dilute solutions 

1 Because to our minds the system soap, dissolved in water is something 
totally different from the system water dissolved in soap. See page 52. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 395 



may not be applied without the greatest reserve. Such laws may 
only be applied to the solutions of protoplasm in water, as to the 
more watery secretions from the body like urine, saliva or sweat. 

2. If, instead of testing the ' 'secretions" in the above experi- 
ments for alkalinity, we analyze them for content of fatty acid 
(in other words, for amount of soap dissolved in the secretion), 
it is found that most soap is dissolved when plain water is filtered 
through the cup and less and less as salt solutions of increas- 
ing concentration are employed. This too has its biological 
parallel. Distilled water can not, for example, be furnished 
secreting cells without damaging them, for the cells tend to dissolve 
in such distilled water. Thus the excessive consumption of dis- 
tilled water makes for the appearance of albumin in the urine. 
To keep a colloid parenchyma (be it soap or protoplasm) from thus 
going into solution, salt must be added to the distilled water. 
This is one of the reasons why all cells are less damaged by a so- 
called physiological salt solution than by plain water. In fact 
in the case of a kidney previously damaged by distilled water (or 
worse still by some powerful "solution" producing agent like an 
acid) the progressive solution of the kidney in the urine (the 
albuminuria) may be cut down by perfusion of the organ with a 
proper salt solution. 1 

3. We wish, finally, to return to the fact that if the rate at which 
distilled water filters through a soap cup is taken as the standard, 
the rate of such secretion from an ammonium chlorid solution is 
less, while that from other salt solutions like sodium, magnesium 
or calcium chlorid, at equivalent concentrations, is greater and 
in the order named. This, too, has its analog in what may be 
observed in animals, and the explanation of what occurs in animals 
may be deduced, we think, from the action of these salts upon soap. 
Generally speaking, all salts tend to dehydrate soaps and this in 
increasing amount with increasing concentration. When sodium 
chlorid is used there is therefore a progressive increase in dehydra- 
tion of the hydrated sodium stearate constituting the soap cup and, 
with the secondary enlargement of the capillary pores consequent 
upon this, filtration is made proportionately easier. When, how- 
ever, a salt capable of entering into double decomposition with the 
sodium stearate is used, there is added to this first effect a second- 
ary one incident to the production of a new soap. The hydra- 

1 See page 648. 



396 



(EDEMA AND NEPHRITIS 



tion capacities of soaps of the commoner fatty acids with different 
bases runs in about the following order: 

NH 4 , K, Na, Mg, Ca. 

(The solubility of these soaps in water also runs in this order.) 
It will now become clear, when equally concentrated solutions 
of these different salts are filtered through sodium stearate, why 
ammonium and potassium salts lead to a lesser secretion of water 
than sodium, and why magnesium and calcium salts lead to a 
greater one, and in the order named. After double decomposition 
and at least partial formation of the corresponding soaps, the 
original capillarity of the hydrated sodium stearate is changed, 
being decreased in the first named, left largely unchanged in the 
middle member, and increased in the last named. 

It was emphasized above that while the "diuretic" action of 
equally concentrated but different salts differs when their basic 
radicals are different, such distinctions are largely missing when 
salts with a common base but different acid radicals are employed. 
In other words, these soap models do not show the greater diuretic 
action of the citrates, tartrates, phosphates and sulphates over 
^hlorids, for example, which do animal kidneys or living cells in 
general. We expected this result as the necessary corollary 
of certain chemical differences between fatty acids and amino-acids 
and the possibilities possessed by the latter of forming longer series 
of different salts. 

The action of different bases upon a fatty acid may be com- 
pared with the action of the same bases upon the polymerized 
amino-acid which we call protein. "Soaps" are formed in both 
instances with their varying hydration capacities. It is our belief, 
in other words, that if we write the formula for any fatty acid as: 

x— COOH 

that the colloid-chemical properties of the different soaps are 
dependent upon the substitution for the H in the above formula 
of the various metal radicals. If now we write the formula for an 
amino-acid as: 

x— COOH 
I 

NH 2 



ABSORPTION, SECRETION— COMPLEX ORGANISM 397 



the effects of the metal radicals are again the same, and the 
colloid-chemical behavior of the pure proteins which are thus 
formed is again of the same kind as in the case of the soaps. In- 
stead of soaps of fatty acids we get "soaps" of proteinic acid, the 
solvation and solution characteristics of both of which are largely 
the same. The fatty acids do not, however, possess the power 
of uniting with acid as do the amino-acids. In the latter instance 
acids may unite with the NH2 groups. In this fashion there can 
then be produced the chlorids, bromids, sulphates, phosphates, 
etc., of the polymerized amino-acids each again possessed of its 
own solubility in water and solvent power for water. Since the 
cells of the living body are the hydrated salts of polymerized amino- 
acids, the various salts may affect them "diuretically" not only 
through their basic, but also through their acid radicals. 



13. Concluding Remarks on Absorption and Secretion. Lymph 
Formation. Vasomotor and Secretory Nerves 

The variable capacity of the body colloids for holding water 
also helps us to understand some of the phenomena of lymph 
formation. It seems to me that the formatuon of lymph is in 
many points entirely analogous to the secretion of urine and gov- 
erned by similar laws. The "secreting membrane" in this case 
is found in the cells and the intercellular substances that separate 
the blood capillaries from the lymph capillaries. 1 It is, of course, 
clear that these cells and their intercellular substances con- 
stitute the bulk of the body tissues. Anything that makes these 
cells with their intercellular substances yield up water increases 
lymph flow. 

Let us first call attention to the fact that an increased arterial 
circulation to a part increases lymph flow. A classic experiment 
in this line is the observation that an increased lymph flow 
from the neck is obtained when the salivary glands are active 
(supplied with much arterial blood). Under such circumstances 
various tissues in the neck are rapidly freed of their carbonic 
(and other) acids. This decreases the capacity of their colloids 

1 Recent histological and physiological studies indicate clearly that the 
lymph circulates through a series of closed tubes as does the blood. The 
old assumption that a direct communication existed between the two (through 
holes) is certainly not correct. 



398 



(EDEMA AND NEPHRITIS 



for water, and so they give it up, in part to the blood, in part 
to the lymph. 

All salt solutions, when injected into the blood in sufficiently 
concentrated solutions, increase lymph flow. When sodium 
chlorid, sodium bromid, etc., are employed, these have to be 
injected in (osmotically) stronger solutions than when sodium 
sulphate, sodium phosphate, etc., are used. The same thing hap- 
pens in experimental diuresis. These experiments on the forma- 
tion of lymph are easily explained by saying that the salts diffuse 
into the tissues and make them give up their water which then 
passes in part into the blood, but in part again, into the lymphatics. 
A similar explanation can be given of the " lymphogogue " 
action of various sugars. Physostigmin and pilocarpin increase 
lymph flow; atropin and morphin decrease it. In the doses 
ordinarily used, the former make in toto for an increased supply 
of oxygen and the more rapid removal of carbonic acid from the 
cells, the latter for a decreased one. While the former means a 
decrease in the capacity of the tissue colloids to hold water, 
the latter means an increase; these in turn mean a giving up 
of fluid to the lymph in the first case, and none available for 
such a purpose in the second. 

A word may not be amiss regarding the useful purpose served 
by the vaso-motor mechanism in this whole problem of absorp- 
tion and secretion. Changes of both a quantitative and a 
qualitative character must of course follow the changes conse- 
quent upon any variation in the caliber of the blood vessels sup- 
plying a part. With blood of a given composition, it is evident 
that with vaso-dilatation more will flow through a part, and 
so the opportunities for absorption or secretion, whether of 
water or dissolved substances, be increased. But such quan- 
titative changes in the blood flow through a part affect at the 
same time the chemical and physico-chemical character of the 
cells in that part, and so a series of qualitative changes in 
the character of the absorption or the secretion may be added 
to the quantitative ones already noted. It is these facts that 
we have to bear in mind when we attempt the analysis of the 
various phenomena that characterize absorption and secretion as 
observed, for example, in a mammal. 

The organs that are predominantly secreting organs (kid- 
ney, salivary glands, stomach, pancreas) are all supplied with 



ABSORPTION, SECRETION— COMPLEX ORGANISM 399 



large arteries, and when these glands are active, their arteries 
are dilated. The supply of highly arterilized blood which makes 
possible the secretion of gastric juice (as it makes possible the 
secretion of urine) makes it impossible at the same time for this 
organ to act as an absorptive organ. And experimentally we 
know the stomach to act indifferently, well in this direction as 
far as water absorption is concerned. Other substances can, of 
course, be absorbed from the stomach (alcohol, salts) and be 
secreted into it (various salts) independently of any absorption 
of water. Failure to absorb water only means, of course, that 
the stomach wall, and the (arterial) blood coursing through it 
is saturated with water — the three phases of the system are in 
equilibrium so far as their water content is concerned. In so 
far as any dissolved substance is not distributed in such a way 
through the three systems as to be in equilibrium, it must move 
(be absorbed) into the stomach wall and the blood, or out of these 
(be secreted) into the gastric contents until the equilibrium is 
established. When the rich supply of arterial blood to a secreting 
organ fails, no secretion occurs, as can be seen particularly well 
in the kidneys, the salivary glands, etc., when their blood supply 
is cut down either through experimental constriction of the arteries 
supplying them, or when the vaso-constrictor nerves are stimu- 
lated. 

It is true that under certain conditions no secretion may 
occur from a gland even when an abundant arterial flow is fur- 
nished the secreting cells, but this is only possible if the normal 
chemistry of the cells constituting the secreting membrane is 
first disturbed, as after poisoning with atropin, which so inter- 
feres with the oxidation chemistry of the cells that they are put 
in a state of lack of oxygen in spite of all that is flowing by them. 

We can also understand the meaning of some of the morpho- 
logical changes observed in the cells of any secreting organ so 
situated as to have alternate periods of rest and activity. While 
the process differs somewhat in different cells, it may be stated 
in general that the cells become larger during rest, and smaller 
during activity. The interpretation of this simple fact as gen- 
erally given is very complicated. Need we say more than that 
they absorb water (become ©edematous) when arterial blood is 
scarce and they cannot get rid of their carbonic acid easily; and 
that they secrete water, that is, shrink, when the carbonic and 



400 



(EDEMA AND NEPHRITIS 



other acids that are produced in cells when oxygen is scarce, 
are removed through a better arterial blood supply? With the 
swelling of the cells during a period of rest there is an accumu- 
lation of granules in the cells. Most extravagant interpretations 
have been made of their physiological significance. Need they 
be anything more than protein (including mucin) precipitates 
occurring in the bodies of the cells because in the period of gland- 
ular rest the reaction of the cell protoplasm tends to move toward 
the acid side? When the granules disappear during glandular 
activity it simply means a reversal of the process — they go back 
into solution as the reaction moves back toward the neutral 
point or the alkaline side. The changes observed during rest 
and activity of the salivary glands, pancreas, etc., therefore 
become similar to the changes of " cloudy swelling," 1 observed 
in the liver or kidney in various pathological states (including 
interferences with the arterial blood supply to the cells making 
up these organs). 

Need we also to continue our belief in " secretory " nerves? 
I think not. We do not know a single secretory nerve effect 
in the complex organism which is not preceded by a vasomotor 
(vasodilatation) effect, and the increased secretion is easily 
explained through the increased oxygen supply furnished the 
gland by this means. The secretory nerves are, in other words, 
identical with the vasomotor nerves. There may be vasodilatation 
without secretion as when defectively oxygenated blood is fur- 
nished, or the gland cells themselves are rendered incapable of 
using the proffered oxygen, but there is no secretion without a 
large arterial blood supply which is furnished some glands con- 
stantly while it is furnished others temporarily through vaso- 
dilatation. 

After what has been said it is evident that no great differences 
exist between the essential nature of absorption and of secretion. 
Secretion is only the mirror of absorption. This truth seems 
simple enough, and yet it cannot be said that it has received 
any special attention from the workers in experimental medicine 
or physiology. And yet it ought to, for absorption and secretion 
in a complex animal bear a reciprocal relation to each other. It 

1 For a discussion of the nature and cause of cloudy swelling, see page 
540, or Marti* H. Fischer: Kolloid-Zeitschr., 8, 159 (1911); ibid., 8, 201 
(1911). 



ABSORPTION, SECRETION— COMPLEX ORGANISM 401 



is because this fact has been ignored that much of our present- 
day confusion exists in this field. 

An adult organism in order to continue alive has to maintain 
a certain constancy of physico-chemical composition. It follows 
that if it absorbs anything it must secrete this again within a 
reasonable time thereafter. It is in this " reasonable time" 
and the conditions that are at the bottom of the fact' that this 
" reasonable time " has to intervene between the absorption 
and the secretion of any substance that makes us lose the con- 
nection between the two, even when we deal with the absorption 
and secretion of substances (water, certain salts) which are not 
chemically changed in the body. When these facts are borne 
in mind, the surprise expressed by some authors that atropin 
or morphin, which decrease various secretions, do not similarly 
decrease absorption from the gut or the peritoneal cavity dis- 
appears. Hardly! These substances favor the formation and 
accumulation of acids in the tissues of the body, wherefore, no 
secretion. We should, rather, discover an increased absorption 
of water after use of these drugs, which, in fact, we do. Other 
anesthetics act like morphin, and other drugs like atropin. When 
we use such agents in our experiments we have to remember 
what they do, and not ignore them when we come to interpret 
our findings. Operations, animal boards and physiological 
apparatus produce collectively effects similar to drugs, so these 
too must not be ignored. It is for this reason, as I stated above, 
that all these procedures must be reduced to a minimum if we 
would complete our analysis of just what constitutes the physi- 
ology and the pathology of absorption and secretion. 

The analysis of the problems of absorption and secretion 
could already be carried with entire safety beyond the limits 
outlined here and in my previous papers, which have had as 
their chief aim the mere establishment of the thesis that the 
colloids and their physical state determine both the quantitative 
and the qualitative character of the absorption and secretion 
of water and dissolved substances by protoplasm. This will 
be done elsewhere. 1 In passing, however, attention must be 
called to the excellent service that will be rendered the further 
analysis of the problem by the theories of the colloid state which 

*See pages 52, 59, 396, 527 and 775 and Martin H. Fisher: Soaps and 
Proteins, New York (1920), in press. 



402 



(EDEMA AND NEPHRITIS 



are becoming progressively more clearly defined. Especially 
helpful to the biological worker must become the conclusions 
of Wolfgang Pauli 1 and his co-workers, 2 more particularly 
Hans Handovsky 3 and Karl Schorr, 4 as well as those of R. C. 
Tolman, 5 whose theoretical deductions regarding the colloid 
state seem broader and less capable of adverse critical attack 
than any yet proposed. 

The theoretical elucidation of the absorption and secretion 
of dissolved substances will necessitate adequate use of Wolf- 
gang Ostwald's 6 work. Ostwald has shown that the math- 
ematical formulas of adsorption are applicable to the process 
of absorption (intoxication) as shown in certain fresh-water 
animals (Gammarus) when they are placed in solutions of 
various kinds. It is evident that these animals swimming 
about in a solution are no differently situated than a group 
of cells, say, in the mucous membrane of the intestine, which 
are bathed by such a solution. But Ostwald has developed 
the biological significance of what represents in a sense the 
mirror image of the adsorption formula, namely, the washing- 
out formula. This may be used to express mathematically the 
" toxic effect " of distilled water upon these animals — an effect 
brought about by the diffusion out into the distilled water of the 
salts contained in the animal. It is evident that the leaching out 
of dissolved substances from the kidney by the pure water origi- 
nally secreted from the organ constitutes the parallel of this 
" toxic effect " of the distilled water on Gammarus. Ostwald 
has further shown that the effect of a solution having but one salt 
dissolved in it is the composite of the adsorption effect of that salt 
plus the washing out effect of all the other salts contained in the 
animal but absent from the solution that is being experimentally 
employed. This phenomenon has its analogue in the experi- 
mental absorption of any pure solution from the intestinal tract 

1 Wolfgang Pauli: Kolloid-Zeitschr., 7, 213 (1910). ^ 

2 Wolfgang Pauli and Hans Handovsky: Biochem. Zeitschr., 18, 340 
(1909). 

3 Hans Handovsky: Kolloid-Zeitschr., 1, 183 and 267 (1910), where 
references to earlier papers will be found. 

4 Karl Schorr: (Cited by Pauli and Handovsky). 

5 R. C. Tolman: Jour. Am. Chem. Soc, 35, 307 (1913); 35, 317 (1913); 
Science, 44, 565 (1916). 

6 Wolfgang Ostwald: Pfluger's Arch., 120, 19 (1907); Kolloid-Zeitschr., 
2, 108 and 138 (1907). Wolfgang Ostwald and A. Dernoschek: Kolloid- 
Zeitschr., 6 (1910). 



ABSORPTION, SECRETION— COMPLEX ORGANISM 403 



of a mammal, for example, in which, as was noted above, there 
is a " secretion " of dissolved substances from the intestinal 
wall into the gut, while the dissolved substance originally intro- 
duced is being " absorbed." 

IV 

MAINTENANCE OF THE CIRCULATING FLUIDS IN 
THE BODY 

1. Why the Blood Remains in the Blood Vessels 

We have up to this point been chiefly interested in the mechan- 
ism by which we manage to get a secretion from the blood, and 
by way of illustration have discussed with particular intensity the 
mechanism by which more or less water may be obtained from a 
kidney. We have seen how a kidney will secrete only as water 
is brought to it, and this in proportion to the amount of "free" 
water furnished. Let us now change our viewpoint, and instead 
of asking how we may get more urine from the blood, ask why 
all the blood is not poured out as urine (or some other secretion) , 
in other words, why does the blood remain in the blood vessels? 1 
This is biologically just as important, and medically and . 
surgically just as practical a question as that of the ways and 
means by which a urinary secretion is maintained and increased 
or decreased. 

The maintenance of a normal circulation is absolutely neces- 
sary in the complex organism. It provides the individual cells 
with the materials necessary for their life, while at the same 
time it carries away the poisonous substances produced by them, 
which, if allowed to accumulate, threaten their existence. What 
is said in these paragraphs holds for both the blood and the 
lymph, but unless otherwise stated, we shall limit ourselves 
to the problem of the circulation of the blood. For the main- 
tenance of a circulation we need a properly working pump and a 
suitable circulating fluid. 

The question of what constitutes a suitable circulating fluid 
may be discussed from two points of view, from a chemical and 

x See Martin H. Fischer: "(Edema," 186, New York (1910); Kolloid- 
chem. Beihefte, 2, 324 (1911); James J. Hogan and Martin H. Fischer: 
Kolloidchem. Beihefte, 3, 385 (1912). 



404 



(EDEMA AND NEPHRITIS 



from a physical. The chemical side will be touched upon but 
incidentally. Our chief interest lies in certain physical aspects 
of the problem. 

Since our experimental studies were instigated by considera- 
tion of some problems in practical medicine, our discussion may 
begin with these. That part of the problem of maintaining a 
normal circulation which has to do with the existence of a suitable 
circulating fluid is usually taken pretty much for granted. We 
shall see later that this is dangerous. The coarser disturbances 
which may affect a circulating fluid like the blood are, however, 
familiar to every clinician and are striking enough. We need 
but call to mind the consequences of hemorrhage. If by accident 
or otherwise one of the larger vessels is opened in man or a labora- 
tory animal, we see following each other in the course of a very 
few minutes all those alarming symptoms which culminate in 
death. 

When now we try to say why this occurs it is quickly brought 
home to us that the most serious mischief done by the hemorrhage 
does not reside in a great loss of red blood corpuscles or in a 
loss of certain of the chemical constituents found in the blood, 
say the hemoglobin or certain salts, but in a diminution in the 
volume of the circulating blood. The proof for such a conclusion 
is easily brought, for to protect or save an animal from the effects 
of hemorrhage it is not necessary to transfuse blood; but trans- 
fusion with water containing various salts (so-called " physi- 
ological salt solution," Ringer solution " or " Locke solu- 
tion ") may do. In fact, the dangers incident to transfusion 
of whole blood have made medical men in practice depend more 
and more upon salt solutions of various kinds and less upon the 
transfusion of blood itself. 

But even though salt solutions of various kinds work excel- 
lently, they do this only for a limited time. In other words, 
it is too often noted that while a physiological salt solution or a 
Ringer solution produces immediately brilliant results, this 
effect wears off in an hour or two so that the individual who has 
been roused from the threatening effects of a great hemorrhage 
begins to sink again, and even though we repeat our injection, 
the improvement in patient or animal is again only temporary. 

It is easy to see why this happens. The injected salt solution 
does not remain in the blood vessels. Proof of this is at hand. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 405 



Not only does the blood pressure attained after the injection 
gradually fall, but the injected fluid leaves the body as urine 
or is taken up by the tissues (an oedema develops) or both. If 
the water could be retained in the blood vessels we should get 
more lasting results from the injection of a salt solution. We 
are now in the heart of the problem and theme of these para- 
graphs. As seen in the experiments on the intravenous injection 
of blood and blood serum already described above, 1 the blood 
remains in the blood vessels (and the lymph in the lymph vessels) 
because the water is all held as hydration water combined with the 
colloids of the blood (and lymph) , and in this form cannot escape as 
a secretion. 

To meet the objection that the blood remains in the blood 
vessels because of some specific property and not simply because 
all its water is held in combination with the colloids of the blood, 
we insert Fig. 128 and Experiments 47 and 48 where water is again 
injected intravenously, but this time in combination with a colloid 
foreign to the blood, namely, gelatin. 

Experiment 47, which describes the intravenous injection of 
a pure 2 per cent gelatin solution, is inserted merely for purposes 
of control. Such a solution yields no rise in urinary output 
• (see Curve b of Fig. 128), but objections may be raised to this 
experiment. As the proto- 
col shows, the animal de- I0 f 
velops hemoglobinuria and 
albuminuria, casts appear in 6 * 



the urine and the urinary 
secretion is very low, in other 
words, it develops a " neph- 




ritis." It could justly be Figure 128. 

charged, therefore, that such 

an animal secretes no water simply because it is nephritic. One 
of the causes of this nephritis resides in the acid properties of 
the gelatin used, but the whole picture cannot be thus explained. 
The pure gelatin solution produces all the signs and symptoms 
following injection of an equal amount of distilled water. The 
injection of this causes no rise in urinary output, but only be- 
cause the destructive action of the water on the blood with 
its consequent interference with the normal oxidation chemistry 

1 See page 336 



406 



(EDEMA AND NEPHRITIS 



of the body more than offsets the diuretic action of the water 
alone. 

There are therefore at least two factors responsible for the 
poisonous effects of a pure gelatin solution, its acid content 
and the retention in its hydration water of those properties of 
distilled water destructive to the blood. This conclusion is of 
importance not only from the standpoint of practical medicine, 
but also from that of the theory of the colloid state. 

We can avoid the practical and theoretical objections to the 
experiment just described by adding a salt to the gelatin solu- 
tion as in Experiment 48. Then there is no hemolysis, no hemo- 
globinuria, no albuminuria, no casts, and the urinary output 
is normal (see Curve a in Fig. 128), This experiment proves 
that water in combination with a colloid (gelatin) remains in 
the blood vessels. 1 

Experiment 47. Injection Fluid: 2 per cent gelatin solution. 
Belgian male rabbit. Weight 1448 grams. Kept on standard mixed 
diet. 

72.4 cc. of the above solution, an amount estimated as equivalent 
to the total blood volume of the animal, are injected into an ear vein 
at the uniform rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


2.15 




Tied down, catheterized, injection begun. 




7.0 


Clear, yellow, no albumin. 


2.30 


0.5 


Clear, yellow. 


2.45 


0.4 


Slightly bloody, albumin. 


2.55 




Injection ended. 


3.00 


0.4 


Somewhat bloody. 


3.15 


0.4 


Bloody, many yellowish casts. 


3.30 






3.45 


0.2 


Same. 


4.00 


One drop 


The color of port wine, many yellow casts. 


4.15 


0.5 


Same. ' 


4.30 


1.4 


Same. 


4.45 


0.8 


Same. 



Animal released. 

Total urine in two and one-half-hour period since beginning of 
injection, 4.6 cc. 

Animal found dead in cage next morning. 

1 H. Roger and Garmer (Soc. de Biol., Mai 4 (1912); Compt. Rend. 
Soc. de Biol., Mai 5 (1912)) have also found an increased urinary output after 
intravenous injection of Locke's solution, but none when gelatin was added 
to this. They conclude that solutions "isoviscid" with the blood do not act 
diuretically but attempt no explanation of the fact. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 407 



Autopsy: Peritoneal and pleural cavities contain a little bloody 
fluid. 

Heart is filled with blood. 
Kidneys, grayish and swollen. 

Experiment 48. Injection Fluid: 2 per cent gelatin in m/8 
NaCl. White male rabbit. Weight 1249 grams. Kept on standard 
mixed diet. 

62.5 cc. of the above solution, an amount equivalent to the total 
blood volume of the animal, are injected into an ear vein at the uniform 
rate of 10 cc. every five minutes. No anesthetic. 



Time. 


Urine in cc. 


Remarks. 


10.45 




Tied down, catheterized, injection begun. 




0.2 


Cloudy, yellow, alkaline, no albumin. 


11.00 


0.2 


Same. 


11.15 


1.5 


Cloudy, yellow, alkaline, no albumin, no blood. 






Injection ended. 


11.30 


1.7 


Same. 


11.45 


3.2 


Same. 


12.00 


9.6 


Same. 


12.15 


2.5 


Same. 


12.30 


2.5 


Same. 


12.45 


2.5 


Clear, no albumin, no blood. 


1.00 


2.5 


Same. 



Animal released in good condition. 

Total urine in the two and one-quarter-hour period since beginning 
of injection, 19 cc. 



If the explanation of the foregoing protocols is correct we 
should be able so to arrange our experiments that water will 
be retained in the blood vessels of an animal or secreted; depend- 
ing upon whether we introduce it in combination with a colloid 
or as " free " water. Such proof must, moreover, be adducible 
in one and the same animal. Fig. 129 shows the results when 
the injection of horse serum (water in combination with a colloid) 
is followed by one of salt solution ("free" water). Curves a, 
b, and c correspond to Experiments 49, 50, and 51, respectively. 
It is strikingly apparent that as long as we inject blood serum 
there is no increase in urinary output, whereas it rises enormously 
as soon as the salt solution is started. 

Experiment 49. Injection Fluids: Horse-blood serum followed by 
m/2 (2.9%) NaCl. White rabbit. Weight 1417 grams. Kept on 
standard mixed diet. 

90 cc. of the serum, an amount equivalent to about If times the 
total blood volume of the animal, are injected into an ear vein at the uni- 



408 



(EDEMA AND NEPHRITIS 



form rate of 10 cc. every five minutes. 60 cc. m/2 NaCl solution 
are then injected in the same way. 



Time. 


Urine 


in cc. 


Remarks. 


10.00 






Tied down, catheterized, injection begun. 







3 


Clear, dark amber, no albumin. 


10.15 





3 


No albumin. 


10.30 


7 


5 


Neutral, faint trace of albumin. 


10.45 


5 





Clear, neutral, albumin, one cast. 

Injection of serum ended and injection of NaCl solu- 
tion begun. 


11.00 


18.0 


Last part clear as water, faint trace of albumin, one cast. 


11.15 


78 





Clear as water, neutral to litmus, faint trace of albumin. 
Injection of NaCl solution ended. 



Animal released in good condition; eats and drinks at once. 
Next morning the animal is alive and well, a 

Total urine in the forty-five-minute period of the serum injection, 
12.8 cc. 

In the next forty-five-minute period of the salt injection, 134.0 cc. 

Experiment 50. Injection Fluids: Horse-blood serum, followed by 
m/2 (2.9%) NaCl. Black male rabbit. Weight 1795 grams. Kept 
on standard mixed diet. 

90 cc. of the serum, an amount equivalent to the total blood volume 
of the animal, are injected into an ear vein at the uniform, rate of 10 cc. 
every five minutes. 90 cc. of the NaCl solution are then injected in the 
same way. 



Time. 


Urine in cc. 


Remarks. 


11 


00 






Tied down, catheterized, injection begun. 









5 


Clear amber, alkaline, no albumin. 


11 


30 


1 


8 


Same. 


11 


45 


3 


8 


Clear amber, alkaline, faint trace of albumin, three casts. 
Injection of serum ended and injection of NaCl begun. 


12 


00 


32 





Last part clear as water, alkaline, faint trace of albumin, no 
casts, no red blood corpuscles. 


12 


15 


67 


5 


Clear as water, neutral, no albumin. 


12 


30 


75 





Same. 

Injection of NaCl ended. 


12 


45 


22 


5 


Same. 


1 


00 


8 





Same. 



Animal released in good condition. 
Next morning is alive and well. 

Total urine in the forty-five-minute period of the serum injection, 
5.6 cc. 

In the forty-five-minute period of the salt injection, 174.5 cc. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 409 



Experiment 51. Injection Fluids: Horse-blood serum, followed by 
m/2 (2.9%) NaCl. Mixed Himalaya rabbit. Weight 1593 grams. 
Kept on standard mixed diet. 

25 grams of blood are taken from the carotid artery, an amount 
equivalent to about one-third of the total blood volume of the animal. 

96 cc. of serum are then injected at the uniform rate of 10 cc. every 
five minutes into an ear vein. This amount is about 1^ times the 
blood volume of the animal. 

60 cc. of the NaCl solution are then injected in the same way. 



Time. 


Urine 


in cc. 


Remarks. 


1.35 






Tied down. Drawing of the 25 grams of blood from the 
carotid artery begun. 


1.55 





3 


Bleeding ended and injection of serum begun. 36 cc. are 
injected in the first five minutes, then at the uniform rate 
of 10 cc. every five minutes. 


2.10 


2 


3 


Clearing, trace of albumin. 


2.25 


3 





Slightly red, albumin, no casts, no red blood corpuscles. 


2.30 






Injection of serum ended and injection of NaCl begun. 


2.40 


7 


5 


Last part clear, faint trace of albumin. 


2.55 


61 





Clear, trace of albumin. 


3.00 






Injection of NaCl ended. 


3.10 


6.30 


Same. 



Animal released; found dead in cage next morning. 

Total urine in the thirty-five-minute period of the serum injection, 

5.3. 

In the following forty-minute period of the salt injection, 131.5 cc. 



In Experiments 49, 50, and 51 the injection of horse serum 
was followed by an albuminuria. This albuminuria is attribut- 
able to the large injections made, in consequence of which the 
circulatory system becomes overfilled. This leads to circulatory 
disturbances which affect the kidneys (and other organs) result- 
ing in the appearance of casts and albumin in the urine. The 
dyspnea caused by such large injections of serum is plain evidence 
of the general disturbance. Interestingly enough it can be made 
to disappear in a few minutes by injecting a strong salt solution, 
for this dehydrates the blood colloids and as the freed water 
escapes through the kidneys the volume of fluid in the blood 
vessels sinks nearer the normal. 1 

iC. H. Neilson: Jour. Am. Med. Assoc., 40, 436 (1913), nas made a 
careful study of the effects of various salines on the high blood pressure shown 
by different types of patients. The salines decrease the blood pressure. 
It is an interesting fact that they do this in the order in which they dehydrate 
colloids. The salines dehydrate the liquid blood, of course, as they do the 
rest of the body and as the volume of circulating fluid in proportion to the 
capacity of the blood vessels for holding it falls, the blood pressure must sink. 



(EDEMA AND NEPHRITIS 




ABSORPTION, SECRETION— COMPLEX ORGANISM 411 



Curves a and b of Fig. 130 are based on Experiments 52 and 
53; they show results similar to those of Fig. 129, except that in 
these experiments the water 
was held in combination with 
gelatin instead of the colloids 
of blood. In Experiment 52 
we used a pure gelatin solu- 
tion, in Experiment 53 a gela- 
tin solution in a weak salt solu- 
tion. What we said above 
regarding the relative toxicity 
of such solutions is true here, 
and the analogous effects on 
the animal show plainly in 
the protocols. 

In Experiment 54 the water 
was held in combination with 
the colloid casein. The casein 
solution was prepared by neu- 
tralizing the ordinary (acid) 
casein prepared by Hammar- 
sten's method with a weak 
sodium hydroxid solution and 
adding enough sodium chlorid 
to bring the final mixture to 
the concentration of a " phys- 
iological " (0.7 per cent) so- 
lution. The effects of a casein 
solution without the sodium 
chlorid are the same as those 
of a pure gelatin solution. 
Fig. 131 based on this ex- 
periment needs no explana- 
tion. Figure 131. 




Hours 



Experiment 52. Injection Fluids: 2 per cent gelatin solution fol- 
lowed by m/2 (2.9%) NaCl. Belgian male rabbit. Weight 1822 
grams. Kept on standard mixed diet. 

91 cc. of the gelatin solution, an amount equivalent to the total 
blood volume of the animal, are injected into an ear vein at the uniform 
rate of 10 cc. every five minutes. 

91 cc. of the NaCl solution are then injected in the same way. 



412 (EDEMA AND NEPHRITIS 



Time. 


Urine 


in cc. 


Remarks. 


9 


50 


2 


8 


Tied down, catheterized. 
Yellow, alkaline, no albumin. 


10 


15 





4 


Injection of gelatin solution begun. 


10 


30 





6 


Cloudy, yellow, alkaline, no albumin. 


10 


45 





3 


Same. 


11 


00 





3 


Same. 

Injection of gelatin solution ended, injection of NaCl 
solution begun. 


11 


15 


5 





Bloody, alkaline, albumin, filled with long, coarse-grained 
casts. 


11 


30 


76 





Pale red, faintly alkaline, trace of albumin, no casts. 

(hemoglobinuria). 


11 


45 


6 


9 


Same. (Rapid breathing.) 
Injection of NaCl ended. 


12 


00 


4 


3 


Hemoglobinuria. 


12 


15 






Animal released, breathing short and rapid, head held high. 


2 


45 






Animal dies. 



Autopsy. — In peritoneal and pleural cavities some bloody fluid 
containing no red blood corpuscles. 

Total urine in forty-five minute period of gelatin injection, 1.2 cc. 
In the forty-five minute period of the salt solution injection, 87.9 cc. 



Experiment 53. Injection Fluids: 2 per cent gelatin solution 
in m/8 NaCl, followed by m/2 NaCl solution. Yellow male rabbit. 
Weight 2083 grams. Kept on standard mixed diet. 

104 cc. of the gelatin solution, an amount equivalent to the total 
blood volume of the animal, are injected into ear vein at uniform rate 
10 cc. every five minutes. 

104 cc. of the NaCl solution are then injected in the same way. 



Time. 


Urine in cc. 


Remarks. 


11.00 




Tied down, catheterized, injection begun. 




2.3 


Dark amber, alkaline, no albumin. 


11.15 


1.5 


Same. 


11.30 


0.8 


Dark amber, alkaline,, faint trace of albumin. 


11.45 


0.4 


Same. 


11.50 




Injection of gelatin ended. 


12.00 


3.0 


Clearing, alkaline, faint trace of albumin, no casts, no blood. 






Injection of NaCl begun. 


12.15 


44.0 


Clear as water, faintly alkaline, no albumin. 


12.30 


72.0 


Same. 






Injection of NaCl ended. 


1.00 


56.5 


Same. 



Animal released in good condition. 
Next morning alive and well. 

Total urine in forty-five minute period of gelatin injection, 2.9 cc. 
In the forty-five minute period of the salt solution injection, 172.5 cc. 



ABSORPTION, SECRETION — COMPLEX ORGANISM 413 



Experiment 54. Injection Fluids: Casein solution made by dissolv- 
ing 8 grams casein and 1.4 grams NaCl in 200 cc. n/30 NaOH followed 
by m/2 (2.9%) NaCl. Belgian male rabbit. Weight 2098 grams. 
Kept on standard mixed diet. No anesthetic. 

104.9 grams of the casein solution are first injected into an ear vein 
at the uniform rate of 10 cc. every five minutes. This is followed by 
104.9 cc. of the NaCl solution injected in the same way. 



Time. 


TTrinp In of* 

\J 1 1UC 111 


Remarks. 


2 


15 


0.4 


Tied down, catheterized, injection begun. 
Amber, acid, no albumin. 


2 


30 






2 


45 


0.2 


Acid, no albumin. 


3 


00 


0.2 


Amber, acid. 

On addition of acetic acid a white precipitate is thrown 
down which disappears on the addition of more acetic 
acid. If this precipitate is filtered off, the filtrate gives 
no albumin reaction on the addition of concentrated 
nitric acid. The acetic acid precipitate disappears 
on heating, but on cooling is again formed. 

No casts, no red blood corpuscles. 


3 


05 




Injection of casein solution ended. 


3 


15 


One drop 


Injection of NaCl begun. 


3 


30 


36.0 


Last part clear as water, faintly acid. 
Albumin reaction as at 3 o'clock. 


3 


45 


60.0 


Clear as water, neutral. 
Albumin reaction as described. 


4 


00 


35.0 


Same. 


4 


15 


4.4 


Same. 


4 


30 


0.2 


Same. 


5 


00 




Animal released and returned to cage. 
Animal dies. 


5 


30 





Mere inspection of the animals during the injection of a 
colloid solution or a salt solution shows that in the first case 
the injected fluid is retained in the blood vessels, while in the 
second it is not. If we palpate the superficial blood vessels 
(veins and arteries of the skin and ear, the carotid and femoral 
arteries) we note that during the injection of a hydrophilic colloid 
solution they become gradually fuller and remain so. As the 
blood vessels become more distended the amplitude of the 
pulse lessens, and this effect persists. Even when the non- 
poisonous blood serum is injected the animal's breathing becomes 
disturbed before long, and if the injection is continued the animal 
dies from mere overdistention of its blood vessels with its result- 
ing mechanical disturbances in the circulation of the blood. 

The injection of a salt solution is not attended by such con- 
sequences. The distention of the blood vessels is not so marked 
and the effect is not lasting. There is no disturbance in breath- 
ing and if a dyspnea was previously induced by distention of 



414 



GEDEMA AND NEPHRITIS 



the blood vessels with a colloid solution it improves. Or if we 
have first brought on a (presumably) fatal hemorrhage and 
then saved the animal by an injection of serum, we may kill it 
subsequently by injecting a concentrated salt solution (which 
again diminishes the volume of the blood in the blood vessels, as 
in Experiment 51). 

Autopsy of the animal also shows that only the colloid solu- 
tion remains in the blood vessels. When an animal has been 
injected with salt solution (especially if concentrated) the 
amount of blood in the heart and large blood vessels is normal 
or even below normal. On cutting through organs like the 
liver or kidney they bleed but little, or are quite dry. But if 
we have injected a colloid solution, the heart and large vessels 
are filled with blood and on cutting through one of the parenchy- 
matous organs it wells out. 

Still other facts show that the colloid solution remains in the 
blood vessels. It simply cannot get out. Its escape from the 
blood vessels, which represent a closed system of tubes, is analo- 
gous to its disappearance from the serous cavities or the gastro- 
intestinal tract. Water bound to a colloid (blood, lymph, gela- 
tin solution, agar-agar, native albumin) cannot be absorbed as 
such by the peritoneum, or the mucosa of the gastro-intestinal 
tract, as previously emphasized, and the same holds for the 
blood in the blood vessels and the lymph in the lymph vessels. 

Finally — and to many physiologists and clinicians this will 
seem most convincing — direct measurements of blood pressure 
show that colloid solutions remain in the blood vessels while 
salt solutions do not. The rise in blood pressure after the injec- 
tion of a 0.9 per cent sodium chlorid solution into a non-anes- 
thetized rabbit is only temporary — in from five to thirty minutes 
the pressure sinks once more to its normal level. At the same 
time the urinary output rises. The same is true in patients. 
The intravenous injection of two or three liters of properly 
prepared salt solution does not change the blood pressure at 
all. If the same amount of water is injected in the form of 
blood serum, or a gelatin solution, the blood pressure rises from 
10 to 25 mm. of mercury and remains there. At the same time 
there occurs no increase in urinary output. Such findings are 
especially marked in the abnormally low blood pressures fol- 
lowing hemorrhage. While salt solutions effect perhaps a tern- 



ABSORPTION, SECRETION— COMPLEX ORGANISM 415 



porary rise in pressure (and for the time being a general improve- 
ment in the .symptoms consequent upon the hemorrhage) a 
permanent rise results from an injection of blood serum. 

2. On the Treatment of Shock 

The foregoing experiments were made in order to formulate 
mofe clearly the principles that must govern us in the treatment 
of those various pathological conditions that are characterized 
by an abnormally low blood pressure. A low blood pressure 
may have many causes; if it becomes especially low it is fatal 
to both man and beast. Why in a given condition the blood 
pressure is low is answered in very different ways by different 
authors. But on the question of therapy all authors agree that 
the maintenance of life becomes possible only if we succeed in 
raising the blood pressure and keeping it raised until the patient 
has overcome the condition that led to the low blood pressure. 

Such a low blood pressure may result from any one or any 
combination of the following causes : 

1. A decrease in the force or number of the heart beats. 

2. A diminution in the volume of the circulating blood. 

3. An increase in the capacity of the blood vessels to hold 
fluid. 

Or to illustrate this in ordinary clinical terms, a low blood 
pressure may result from a weakened heart muscle (myocarditis) ; 
from a hemorrhage, or a loss of the watery constituents of the 
circulating blood (oligemia) ; from a vasodilatation due either to 
a loss of tone in the blood vessel walls themselves or to impair- 
ment of the nervous (so-called vasomotor exhaustion) or chemical 
mechanisms (loss of the active principle of the suprarenal bodies 
from the blood) which are in part or wholly responsible for the 
maintenance of this tone. 

In these paragraphs we shall disregard the question of failure 
of the heart itself as responsible for a pathologically low blood 
pressure and discuss merely the principles involved in our ordi- 
nary therapeutic attempts at restoring a low blood pressure to 
normal by introducing fluids intravenously. 

The simplest problem of low pressure is presented by the 
ordinary cases of severe hemorrhage. We have learned why 
injection of a "physiological" salt solution into such patients 



416 



(EDEMA AND NEPHRITIS 



is so often disappointing. Only by injecting a suitable colloid 
solution can we expect to bring up the pressure and have it stay up, 
for only such remains in the blood vessels. What kind of a col- 
loid solution can we use and which is best fitted for the purpose? 

After what has been said it is self-evident that the best 
transfusion fluid is whole blood. But the obvious difficulties 
and dangers attendant upon the carrying out of a man to man 
blood transfusion limits its usefulness. The liquid of next 
choice for perfusion is that which most nearly approaches blood, 
namely, blood serum. Human blood serum is, however, difficult 
to obtain. The possibility of getting a human colloid solution 
that will stay in the blood vessels resides in the use of hydrocele 
fluid and of the ascitic accumulations from cases of heart disease. 
Such fluids can be drawn when opportunity offers into sterile 
containers and the serum separated from the fibrin clot by the 
methods employed in collecting horse serum. The use of the 
serum from human milk is also to be counted in here. Certain 
dangers are, of course, attendant upon the use of any of this 
human material, but upon these not overly much emphasis is 
to be laid, for perfusion is not at present employed in cases that 
are not desperately ill. 

It would be ideal if we could obtain a pure colloid solution 
for intravenous injection from other than human sources. But 
the number of available substances is very small and their use 
always connected with some danger. The only blood derivative 
seems to be horse serum. The danger incident to the intravenous 
injection of even large amounts of this appears small in com- 
parison with the certainty of death in cases where we are inclined 
to resort to such transfusion. 

During the past seven years James J. Hogan 1 has made 
good use of properly prepared gelatin solutions in cases of 
hemorrhagic, surgical and toxemic shock. The first to aid him 
by trying gelatin solutions in surgical v patients in whom death 
seemed the only prospect was B. F. Alden. 

Gelatin solutions intended for intravenous use must be pre- 
pared only from the purest gelatin. The ordinary gelatins are 
likely to contain much acid and the products of protein decom- 
position, which when injected intravenously are highly poisonous. 

1 James J. Hogan: Personal communication (1913); see also Jour. Am. 
Med. Assoc., 64, 721 (1915). 



ABSORPTION, SECRETION— COMPLEX ORGANISM 417 



All preparations of gelatin should be tested for these substances. 
In any case they should be thoroughly washed, and if conveniences 
for so doing are available, in running, sterilized, distilled water. 
An amount of moist gelatin the equivalent of 25 grams of the 
dry material is then placed in 1000 cc. of freshly distilled water 
containing 10 grams of sodium chlorid and 2 grams of sodium 
carbonate crystals (Na2C03 -lOH^O.) The whole is then auto- 
claved for an hour at 120° C. The gelatin solution must be 
prepared exactly as here described, otherwise trouble will be 
encountered from the fact that, as ordinarily done, the heating 
necessary to sterilize the gelatin properly decomposes it and so 
destroys the very properties for which it is used. 

The following cases taken from James J. Hogan's series may 
serve as illustrations of what has been said. 

Case L — (Dr. B. F. Alden, San Francisco.) A. F., a 39-year old 
Italian laborer, had always been in good health. On March 3, 1913, 
he was brought from the country into the French Hospital, the victim 
of a severe accident which had occurred the day before. A tree limb 
had fallen across his right leg, crushing the upper end of his tibia, and 
the head and lower third of the shaft of the femur. All structures 
beneath the skin, with the exception of the semitendinosis tendon, 
had been completely severed. There existed also a compound frac- 
ture which, however, did not bleed, as all vascular communication 
had been severed above. The left tibia and fibula were fractured. 
Hemorrhage had been excessive, as practically no attempt had been 
made to control it. 

The patient was in a state of profound shock. He was almost exsan- 
guinated and showed a small, rapid, soft, radial pulse with cold extremities, 
excessive thirst, and shallow and rapid respiration. Blood was oozing 
from the lacerated wound about the knee. Strychnin, normal salt 
solution subcutaneously, gelatin subcutaneously, and the usual hemo- 
static measures were all used without improving the general state of 
the patient. Under one-half grain tropococain anesthesia, admin- 
istered intraspinally, the integument, which with a single tendon alone 
united the crushed leg to the patient, was severed. The clotted blood 
and crushed bone were removed and the large vessels in the stump 
rapidly ligated; the wound was dressed and the patient rushed to bed 
where his head was placed low and surface heat applied. The pulse 
could now no longer be obtained at the wrist, and as death seemed 
imminent it was felt that an intravenous injection of a gelatin solution 
was justified. 

500 cc. were given. As there was no radial pulse at the beginning 
of the injection an accurate blood-pressure reading could not be made. 
The needle of a Tycos instrument oscillated at 90 mm. While the 



418 



OEDEMA AND NEPHRITIS 



injection was being made the radial pulse gradually returned and an 
hour later the blood pressure measured 125 mm. During the same 
time the pulse rate dropped from 130 to 88. The pressure was main- 
tained, rising slightly from day to day, until on the tenth day after 
the infusion it measured 145, while at the same time the pulse gradually 
dropped to 78. The pressure now gradually declined to 125 mm. 
and the pulse to 72. The patient made an uneventful recovery. 

Case II. — (Dr. D. N. Richards, San Francisco.) Mrs. E. S. R., 
entered St. Francis Hospital July 2, 1913, at 5.30 p.m. at full term and 
in labor. Regular pains contained until 4.15 a.m. when ether was given 
and she was delivered of a female child. The placenta was expelled 
at 5.10. This was followed by profuse bleeding, which continued until 
the patient was practically exsanguinated. At 6 a.m. the radial pulse 
could scarcely be felt. Her pulse was 140, her blood pressure 
(verified by Drs. Richards and Fraser) 58 mm. As her condi- 
tion was considered alarming, an intravenous injection of 750 cc. of 
gelatin solution was given. The blood pressure rose to 118 mm. within 
an hour, her pulse fell to 100, and her general condition improved 
greatly. For the following four days the pressure varied between 
105 and 110 mm., the pulse between 85 and 100. The patient made a 
good recovery, leaving the hospital July 17.. 

Case III. — (Dr. B. F. Alden, San Francisco.) J. P. G., a 46-year 
old Frenchman, was operated upon by an associate on February 7, 
1913, for a ruptured appendix. A suppurative peritonitis with two 
fecal fistulas, one into the cecum, the other into a loop of the ileum 
resulted. On April 15 the openings in the gut were repaired with Con- 
nel's interrupted sutures of silk covered with continuous Lembert catgut 
sutures. No excessive bleeding was noticed at the time of the opera- 
tion, but one of the Connel sutures must have lacerated a large vessel 
from which an active hemorrhage into the lumen of the gut resulted. 
On April 16 a lowered blood pressure with symptoms indicative of 
hemorrhage were observed. The outer wound was opened and the 
intestinal site explored, but as no serious bleeding was found the gut 
was not disturbed. The wound was repacked with gauze. On the 
morning of April 18 a large bowel movement of coagulated blood was 
observed. In the meantime the patient had declined, steadily. 10 cc. 
of horse serum were injected subcutaneously. A second blood stool 
containing a large amount of fresher blood occurred, when another 
10 cc. of horse serum and 300 cc. of physiological salt solution were given. 
The patient continued to decline, exhibiting all the alarming symptoms 
of active hemorrhage. At 3.30 p.m. on April 18 the patient was reported 
dying. He was pulseless at the wrist. Oscillations in a Tycos instru- 
ment were observed at 80 mm. An immediate intravenous injection 
of 500 cc. of gelatin solution was ordered. Half an hour later the 
patient's pulse had dropped from 156 beats to 138 and had gained in vol- 
ume, strength and regularity. The blood pressure rose to 110 mm. and 
by the following morning it was 140 mm. This pressure persisted while 



ABSORPTION, SECRETION— COMPLEX ORGANISM 419 

the pulse rate within three days gradually fell to 74. An uninterrupted 
convalescence followed and at the present time this patient is well. 

Case IV. — (Drs. W. B. Coffey and C. A. Walker, San Francisco.) 
Mr. B. entered St. Francis Hospital July 26, 1913, having been ill 
for four days. The patient showed marked evidences of general intoxica- 
tion. Examination revealed tenderness in the region of the appendix.. 
An immediate operation was performed which revealed a ruptured 
appendix with marked, circumscribed peritonitis. The patient showed 
great shock after the operation. A 0.9 per cent sodium chlorid solution 
was dripped into the rectum throughout the day following the opera- 
tion. The patient did not rally. His pulse became progressively weaker 
and rose to 130, while his blood pressure fell, until at 9.30 p.m. it meas- 
ured 86 mm. As death seemed the only outcome, gelatin solution was 
given intravenously. This was started at 9.50, the blood pressure at 
this time measuring 85 mm., the pulse 128. The following records 
show the rise in blood pressure during the injection: 

After 150 cc. it was 96 mm. 

" *250 " " 110 " 

" 400 " 11 128 " 

" 500 " " 132 " 

As this pressure was deemed sufficiently high the injection was stopped. 
The patient's general condition improved at once, his radial pulse filling 
out and the rate dropping to 90. The following morning his blood 
pressure was 119 mm., his pulse 90. That afternoon the pressure rose 
to 128 mm. while the pulse dropped to 85. The pressure remained 
while the pulse gradually returned to normal. The patient made an 
uninterrupted recovery. 

Case V. — (Dr. B. F. Alden, San Francisco.) M. C, a 35-year old 
native of France, because of an empyema of the left thorax following 
a lobar pneumonia, was transferred to the surgical service from the 
medical side May 20, 1913, for a thoracotomy. Before he was brought 
to the operating room the patient showed the weak, thready pulse, rapid 
respiration, extreme pallor, drawn face and cold and clammy extremities, 
ears and neck of profound shock. When placed on the operating table 
the patient seemed in extremis and was practically pulseless. Because 
of this no proper blood pressure reading could be made. The anesthetist 
advised against the use of an anesthetic. As it was agreed that the 
patient would die, 500 cc. of gelatin solution were injected into the 
median basilic vein. The incision was made without anesthetic as the 
patient was unconscious. Within ten minutes after beginning the per- 
fusion a perceptible radial pulse was noted and this gradually improved 
in quality. A section of the eighth rib was now removed and drainage 
of the pleural cavity effected. The patient recovered consciousness 
while on the operating table and his blood pressure rose to 118 mm. 
It contained to mount until it reached 154 mm. the following day. At 



420 



(EDEMA AND NEPHRITIS 



the same time the pulse rate fell from 135 to 106. Two days later the 
pressure sank to 106 mm. while the pulse mounted to 136. As the 
drainage was found to be inefficient, by reason of adhesions in the pleura, 
the patient was reoperated under nitrous oxid and oxygen anesthesia. 
This was done without difficulty. The pressure then again rose to 126 
mm. and remained there while the pulse fell back to 100. The patient's 
general condition gradually improved and after a prolonged convales- 
cence he left the hospital. 

It can, of course, be foreseen that what may actually be 
accomplished through gelatin transfusion in any case of low 
blood pressure depends upon the intensity, persistence and nature 
of the factors responsible for it. Viewed in this light, it is not 
remarkable that Hogan's experience thus far has seemed to indi- 
cate that cases of shock consequent upon simple hemorrhage 
are most easily relievable. Even those which showed extreme 
degrees of anemia rallied. Shock consequent upon injury or a 
surgical operation in the ordinary " clean " case seems to be 
controllable almost as easily. Least hopeful are the septic cases 
where the low blood pressure is in large measure dependent 
upon a heart suffering from the general intoxication. This is 
illustrated in Case VI : 

Case VI. — (Drs. W. B. Coffey and C. A. Walker, San Francisco.) 
Mr. C, a 32-year old laborer, was brought into St. Francis Hospital 
at 1 p.m. July 25, 1913, with the diagnosis of a ruptured typhoid ulcer. 
He had had typhoid since July 1. It was felt that the patient could 
not live through an operation. The blood pressure was 65 mm. and as it 
was believed that the patient would certainly die, an intravenous infusion 
of gelatin solution was started at 2 p.m. After 300 cc. had been injected 
the pressure rose to 90 mm.; after 400 cc. to 96 mm.; after 500 cc. to 
99 mm. At this point the abdomen was opened under local anesthesia 
and found filled with fluid, fecal in character. The opening in the 
small intestine was quickly located and closed. The gelatin perfusion 
was continued during the operation, the blood pressure rising steadily 
even during operation as follows: after 600 cc. had been injected it was 
]06 mm.; after 700 cc. it was 108 mm.; after 850 cc. it was 108 mm. 
This higher pressure continued until 6.10 p.m. when he showed signs 
of a rapidly falling pressure and died. 

In closing these paragraphs we would like to have it clearly 
understood that intravenous injections of proper colloid solutions 
are not at once to be accepted as panaceas for shock. In the 
clinical case every effort must be made to discover and meet 
the factors responsible for a weakened heart action, a lack of 



ABSORPTION, SECRETION— COMPLEX ORGANISM 421 



tone in the blood vessels themselves (not as important as usually 
believed and then only terminally) and a diminution in the 
volume of the circulating blood. The monumental studies of 
Yandell Henderson have taught that the last named is of 
great importance and determined, in good part at least, by an 
abstraction of water from the blood by the colloids of the tissues, 
which in conditions leading to shock develop an increased avidity 
for it. We have learned how such avidity may under normal 
circumstances and in oedema be decreased with alkali, salts and 
sugar, and so it is not surprising that this fact may be used to 
advantage both in the prophylaxis and in the treatment of shock. 

Our discussion has thus far considered mainly the use of trans- 
fusion mixtures for a raising of the blood pressure in those simplest 
cases in which shock is the consequence of mere hemorrhage. We 
meet a threateningly low blood pressure also, however, under 
circumstances in which a diminution in the volume of the circu- 
lating blood is brought about by more indirect means. A loss in 
blood volume associated with a low blood pressure may follow 
injury or a surgical operation (traumatic or post-operative shock) 
and is a common finding in the acute or chronic poisonings 
(the toxemic shocks of the infectious diseases). Under all these 
circumstances it is not sufficient merely to fill up the blood 
vessels with more fluid, even if a proper colloid solution is used, 
but the conditions making for the low blood pressure must also 
be met. 

Yandell Henderson 1 has made the keen, and to us correct, 
suggestion that the decrease in volume of the circulating blood 
under such circumstances, which is the chief reason for the 
fatal issue, is brought about through an extraction of the 
watery constituents from the blood by the tissues. The 
tissues are able to do this in shock because, by a series of ante- 
cedent changes resulting in disturbances of their respiration, they 
have been brought into a state of oxygen lack followed by an abnor- 
mal production and accumulation of acids through which the 
capacity of the tissues to absorb water is increased. The tissues, 
therefore, take the watery constituents from the circulating 
blood and thus decrease its volume. If enough is taken out, a 

Yandell Hendekson: Am. Jour. Physiol., 27, 167 (1910); where 
references to his earlier papers may be found. 



422 (EDEMA AND NEPHRITIS 



critical point is reached which, once attained, is necessarily fatal, 
according to Yandell Henderson's views. 

We are inclined to believe that the state of the patient under 
such circumstances is indeed a serious one, but we do not believe 
that it must necessarily prove fatal. It is not sufficient, however, 
in such cases to meet the low blood pressure through mere injec- 
tion of a physiological salt solution or even a proper colloid mix- 
ture, for even the latter is in part robbed of its water, as is ordinary 
blood and by the same means. Even though colloid mixtures work 
better than simple salt solutions, it is necessary in all instances 
to overcome the tendency of the tissues to take the water from 
the blood. The principles that must guide us are simple enough. 
We need to neutralize the acids (and like compounds) which have 
been produced or which have accumulated in abnormal amounts 
in the tissues and to decrease their effects upon the tissue colloids, 
— in other words, we must reduce the swelling of the tissues. We 
do the former by giving the patients alkali, the second by the 
administration of salts. Both are easily accomplished in that we 
administer by mouth, by rectum or intravenously a properly 
prepared hypertonic sodium chlorid-sodium carbonate mix- 
ture. 1 

Through such procedures the tissues are kept from taking more 
water from the blood stream. As a matter of fact, they give 
off water which passes into the blood and so becomes available for 
secretion. The secretions which during shock have fallen in 
amount or perhaps have ceased entirely may therefore increase or 
begin anew. Through increase in blood volume the blood pressure 
also rises for a time. It may not, however, remain increased, for 
the reasons previously emphasized. The hypertonic salt solu- 
tion with its sodium carbonate will work therefore for only an hour 
or two. When, however, we have succeeded in overcoming in 
this fashion the tendency of the tissues to extract water from the 
blood we may inject a proper colloid mixture, for it is now 
probable that this will be retained in the blood vessels and so 
maintain the blood pressure at a higher level for a longer period of 
time. 



1 See page 676. 



ABSORPTION, SECRETION— COMPLEX ORGANISM 423 



3. Critical Remarks on Shock 

I have allowed the above paragraphs to stand as originally 
penned because the Great War brought with it a renewed dis- 
cussion of the nature of shock and its treatment. Innumerable 
papers have appeared on the subject, but scarcely any refer to what 
is written above or when such reference is made it is only for pur- 
poses of adverse criticism. This is a matter of interest because 
the authors of these papers in their practical recommendations 
bring forward only such as are the necessary consequences of the 
colloid-chemical notions of water absorption expressed above. 
While denying the theory, these authors therefore accept in their 
practical conclusions all the principles outlined above. Even when 
their misquotations of me are ignored and also the contradictions 
and self-contradictions in the work of the individual observers, 
they still agree among themselves on the following points. 

The authors accept quite generally a low blood pressure as 
the criterion of shock. For its treatment they hold that a restitu- 
tion of the volume of the circulating blood is the most important 
single element to be satisfied. To obtain permanent results a 
colloid solution of proper composition is demanded. As palliative 
measures they agree as being of assistance warmth, rest and food 
(particularly dextrose), air, delay in the use of general anesthetics, 
delay in the institution of major surgical operations, the admin- 
istration of nitrous oxid-oxygen as the anesthetic of choice, and 
proper alkalinization. The Special Investigation Committee of 
the British Medical Research Committee, 1 for example, give as 
"practical corollaries" of their studies the following: (1) 1 'Restor- 
ation of the volume of blood. . . is therefore the object to be 
aimed at." (2) ' Transfusion of whole blood is probably the 
measure likely to have a successful result in the largest proportion 
of cases." (3) "Infusion of gum-saline solution will be almost as 
effective." (4) "Sodium carbonate may be given separately by 
mouth, rectum, or, if necessary, by cautious intravenous injection." 
(5) "Administration of bicarbonate might appear, therefore, to 
have some rational basis as a preliminary to operation." 

W. B. Cannon 2 observes the shocked to show a low alkali 
reserve in the blood and recommends the avoidance of operations 

^ayliss, Bainbridge, Cannon, Elliot, Starling, etc.: Report No. 7. 
— Acidosis and Shock, 38, London (1918). 

2 W. B. Cannon: Jour. Am. Med. Assoc., 70, 531 (1918). 



424 



(EDEMA AND NEPHRITIS 



upon such individuals. Later 1 with John Fraser and E. M. Col- 
well 2 under "preventive treatment" he recommends alkaline 
injections before operations (which he finds raise the blood pres- 
sure) and as the "ideal injection fluid for shock cases" a solution 
"with colloid added" preferring "one containing sodium bicarbon- 
ate and 6 per cent acacia." E. H. Starling 3 thinks similarly, 
noting also that shocked individuals show "acidosis" as evidenced 
by a low alkali reserve which he holds should be combated with 
alkali, recommending for the purpose the intravenous injection 
of 500 cc. 2 per cent sodium bicarbonate with 5 per cent acacia. 
G. E. Sutton, 4 in addition to mechanical fixation of broken bones, 
uses 2 per cent sodium bicarbonate injections and transfusion of 
whole blood in small amounts. 

These ideas have all been expressed and employed for more 
than a decade past by my medical and surgical associates. 

The observation of the various authors that simple sodium 
chlorid solutions, simple solutions of alkaline salts or hypertonic 
alkaline solutions produce only temporary alleviation or, in the 
case of the last named, an actual further fall in blood pressure 
contains nothing new. 5 

As the above paragraphs indicate, there is also nothing original 
in their suggestion that a hydrophilic colloid solution alone pro- 
duces more lasting results. Under this heading, transfusion with 
whole blood is universally accepted as the best procedure when 
blood is available — as we ourselves first pointed out. The diffi- 
culties of always obtaining such has made imperative the consid- 
eration of substitute colloid mixtures. P. Fiaschi 6 and F. C. 
Mann 7 report satisfactory results following the injection of 
gelatin mixtures. C. C. Guthrie 8 found some colloid necessary 

1 W. B. Cannon, John Fraser, E. M. Colwell: Jour. Am. Med. Assoc., 
70, 618 (1918). 

2 John Fraser and E. M. Colwell: Jour. Am. Med. Assoc., 70, 520 
(1918): E. M. Colwell: ibid., 70, 607 (1918). 

3 E. H. Starling: Arch. Med. Beiges, 71, 369 (1918). 

4 G. E. Sutton: Brit. Med. Jour., 2, 368 (1918); see also Brechot and 
Claret: Bull, de l'Acad. de Med., Paris, 79, 404 (1918); G. Blechmann: 
Paris Medical, 8, 38 (1918); W. B. Cannon, Progres Medical, 33, 290 (1918). 

5 See page 483. Also C. H. Neilson: Jour. Am. Med. Assoc., 60, 436 
(1913); James J. Hogan: Lancet-Clinic, 113, 6 (1915). 

s 6 P. Fiaschi: Communication to the War Office and Admiralty of Great 
Britain (1915). 

7 F. C. Mann: Jour. Am. Med. Assoc., 71, 1187 (1918). 
8 C. C. Guthrie: Jour. Am. Med. Assoc., 71, 1607 (1918). 



ABSORPTION, SECRETION— COMPLEX ORGANISM 425 



but preferred acacia. Other observers found gelatin to be no 
better than similar volumes of salt solution. Their disappoint- 
ment must be attributed to the use of poor grades of gelatin or such 
as were contaminated with protein split products — the dangers of 
using which Hogan and I pointed out years ago. W. M. Bayliss, 
who . as late as 1915 criticised adversely the colloid-chemical 
notions of water absorption, 1 accepts the whole theory in principle 
with his suggestion that 6 per cent acacia gum solutions be used to 
restore blood volume in shocked individuals. 2 

The palliative measures suggested are also old, being merely 
measures which either (1) prevent the development of acid and 
like products in the body or (2) tend to neutralize such as have 
been formed, so as to increase the margin of safety for the afflicted 
individual. Cold and muscular fatigue favor, for example, the 
development of lactic and other acids while warmth and rest inhibit 
such. Pain, all anesthetics and surgical operations also lead to 
acid intoxication. Even the substances used to save patients, 
like morphin, cocain, novocain, etc., by themselves act in this 
direction. When a general anesthetic must be employed, that 
which acts most quickly and which is subsequently lost most 
rapidly is obviously best, especially when associated with high 
oxygen intake, — hence the preference for nitrous oxid-oxygen 
anesthesia. 

It is absurd to argue whether shock produces "acidosis" or 
"acidosis" produces shock. An abnormal accumulation of acid 
within the body (except in its first and small doses) is followed by 
vaso-dilatation, softening of the blood vessel walls and decrease 
in the effectiveness of heart muscle contraction. These things 
in their turn make for defective blood circulation and secondaiily 
for more acid production in the tissues suffering from oxygen 
lack. 

As substances similar to the- acids in their action upon the 
colloids of the tissues, I have often stressed the amins. Peptone 
shock and histamin shock are examples of this class and Bayliss' 
"wound shock," which he himself suggests as probably due to 
amins, falls in this category. At present we know only oxygen to 

1 W. M. Bayliss: Principles of General Physiology, 100, 116, London 
(1915). 

2 W. M. Bayliss: Intravenous Injection in Wound Shock, London (1918); 
Brit, Med. Jour., 1, 553 (1918). 



426 



(EDEMA AND NEPHRITIS 



be of service in the destruction of these compounds and only high 
concentrations of various carbohydrates as effective against the 
action of these substances upon protoplasm. Hence the impor- 
tance of a plentiful air supply and a charging of the system with 
carbohydrates. 



PART FIVE 



THE COLLOID-CHEMICAL THEORY OF WATER AB- 
SORPTION AND SOME PROBLEMS IN BIOLOGY, 
PHYSIOLOGY AND PATHOLOGY. 



PART FIVE 



THE COLLOID-CHEMICAL THEORY OF WATER AB- 
SORPTION AND SOME PROBLEMS IN BIOLOGY, 
PHYSIOLOGY AND PATHOLOGY. 



I 

TURGOR, PLASMOLYSIS AND PLASMOPTYSIS 

In the earlier pages of this volume, when we were first placing 
our medically interesting problem of oedema, experiments were 
described which not only make this a problem of the cells, but 
it was pointed out that cedema really represents only one extreme 
of a series of phenomena common to all cells, vegetable as well 
as animal. To a brief consideration of these which are found 
grouped under the general headings of turgor, plasmolysis and 
plasmoptysis we shall now turn. 

By turgor the plant physiologists understand the normal 
rigidity of the plant cell as determined by a normal or physio- 
logical water content. When by any means the protoplasm 
of the cell is made to shrink away from the morphological (cellu- 
lose) cell wall, the cell is said to be plasmolyzed. When, on the 
other hand, the protoplasm is made to swell so that the cell wall 
is ruptured, plasmoptysis is said to have resulted. The animal 
physiologists have not used these terms in such a strict sense. 
In the use of the term turgor they agree with the plant physiolo- 
gists. The term plasmoptysis they do not generally employ at 
all, and under the heading of plasmolysis they not only consider 
all the more marked variations in the size of cells both in the way 
of a decrease or an increase, but also certain phenomena which 

429 



430 



(EDEMA AND NEPHRITIS 



have become associated with such variations in size, as, for 
example, loss of coloring matter by the red blood corpuscles 
(hemolysis). These distinctions in terms must be borne in mind 
if confusion is to be avoided. To prevent ambiguity in the 
following paragraphs we will in each case first define our terms. 

The reason why the phenomena of turgor, plasmolysis and 
plasmoptysis are brought up in this volume is because discussion 
of their essential nature has not as yet been brought to a satis- 
factory conclusion. For this reason the following paragraphs 
which bring a unifying explanation for many of the apparently 
disconnected and contradictory experimental facts bearing on 
the problem are not out of order. Again will we find ample 
evidence of the important role played by the colloids and thus 
see an application made to problems considered essentially 
physiological of certain principles which we have previously 
discussed under headings considered characteristically patho- 
logical. 

II 

ON THE ABSORPTION OF WATER BY SPERMATOZOA, EPI- 
THELIAL CELLS AND WHITE BLOOD CORPUSCLES 

In the attempt to establish the validity of the laws of osmotic 
pressure for certain physiological and pathological manifestations 
of water absorption, biologists have been particularly eager to 
work with material which on experiment was found to approximate 
most closely the behavior demanded by theory. It is for this 
reason that certain plant cells and the red blood corpuscles have 
been the subject of more exhaustive study so far as their behavior 
toward water absorption is concerned than any other cells. The 
reason why just these cells should have approximated obedience 
to the laws of osmotic pressure more perfectly than most others 
that have been studied may appear later. But even these chosen 
cells show such great exceptions to the behavior demanded by 
theory that it is impossible to escape the experimentally well- 
grounded conclusion that most, if not all, cells do not follow the 
laws of osmotic pressure. The attempts that have been made 
to harmonize the observed behavior of various cells with that 
demanded on the theory that cells represent osmotic systems 
are ingenious, but we can scarcely believe sufficiently supported 



BIOLOGICAL APPLICATIONS 



431 



by experiment to.be convincing. For the most part the explana- 
tions given are complicated, which constitutes in itself a threaten- 
ing feature when the explanation of any natural phenomenon 
is hazarded. What strikes one as particularly encouraging about 
the colloid idea of water absorption is its simplicity, and the 
breadth of water absorption phenomena to which it may be applied 
without apparent experimental or theoretical objection. 

In a preceding part of this book we tried to show how the 
absorption of water by the cells of muscle, the eye, the central 
nervous system, the kidney and the liver is essentially a function 
of their colloid state. What was said regarding these cells is 
also true regarding spermatozoa, white blood corpuscles and the 
epithelial cells of the bronchi, intestine, bladder and esophagus. 
We need not enter into the detailed experimental findings 
on this subject which may be found in H. J. Hamburger's 1 
excellent work. We again encounter no difficulty in explain- 
ing the experimentally observed facts when "we call to mind 
the effect of acids, alkalies, salts, and these in mixture upon 
the swelling of (hydrophilic) protein colloids. All the cells 
mentioned swell if placed in distilled water. This fact, which 
has always been interpreted as due to differences in osmotic 
pressure, is really to be explained by remembering that under 
the conditions prevailing in these experiments the cells produce 
acids which increase the capacity of their colloids for holding 
water. A second factor is found in the diffusion of at least 
some salts out of the cell, for the higher the concentration of 
the neutral salts in a colloid the less does it swell. 2 

1 H. J. Hamburger: Osmotischer Druck und Ionenlehre; 3, 2 to 33, 52; 
2, 400 to 432, Wiesbaden (1904). 

2 The question of the antagonism between acids and neutral salts has 
given rise to meaningless priority claims. In biological material it was 
first discovered by H. J. Hamburger: Arch. f. (Anat. u.) Physiol., 513, (1892); 
153 (1893); Zeitschr. f. Biol., 28, 405 (1891);. ibid., 35, 252, 280 (1897), when 
he noted that it required a higher concentration of salt to prevent swelling 
and lysis of various body cells when acid was present than when such was not 
the case. He also noted that sulphates were more powerful in this regard 
than chlorids. Hamburger explained his findings in the terms of osmotic 
pressure saying, in essence, that the acid acted by increasing the intracel- 
lular osmotic pressure and that an increased salt concentration was therefore 
needed about the cell to counteract it. Other writers have since Ham- 
burger's work claimed both the discovery of the fact and the explanation. 

So far as I know I was the first to observe the general antagonism between 
acids (and alkalies) and neutral salts on the hydration capacity of protein 



432 



(EDEMA AND NEPHRITIS 



The direct swelling effect of acids, including carbonic, is readily 
understood. Acids always bring about the greatest amount 
of swelling in (protein) colloids, and they are found to do this 
also in this biological material. The effect of alkalies is variable. 
Sufficiently dilute alkalies inhibit the swelling of spermatozoa 
in water (through the combined effect of neutralization of the acid 
formed in the spermatozoa and the production of salts) and of 
epithelial cells and white blood corpuscles suspended in water, 
salt solution, sugar solution or serum. The alkali neutralizes 
the progressive production of acid in these cells, as this occurs 
under the conditions of the experiments (for example, separation 
from an adequate oxygen supply, as when the epithelial cells 
are scraped off a mucous membrane). In some concentrations 
and in some cells a greater swelling is produced by alkali than 
by any other chemical except an acid. The less evidence there 
is of a production of acids in a cell or a tissue used for such experi- 
ments as we are describing, the greater the power of alkalies to 
make them swell. This is because when much acid is produced 
the alkali is largely neutralized so that in the end we really observe 
the cells swelling in a low concentration of alkali with much salt 
(formed through neutralization); while when little or no acid 
is produced the cells are swelling in alkali with a little salt (that 
normally found in the cell). All the cells mentioned in this 
paragraph swell less in any salt solution than in distilled water. 
With every increase in the concentration of the salt there comes 
a progressive decrease in the amount of the swelling. At a certain 
concentration the cells maintain for a variable length of time 
what is considered their " normal " volume. If the concentration 
is increased beyond this they shrink. In this brief description 
are exemplified all that is contained in the terms plasmoptysis, 
turgor and plasmolysis as understood by the plant physiologists. 
Impossilbe as it is to understand these phenomena on the basis 
of osmotic pressure, equally easy is it to see in them a perfect 
parallel of (hydrophilic) protein colloids swelling in a dilute 
acid or alkali in the presence of variable amounts of different 
salts. 

colloids (Am. Jour. Physiol., 20, 330 (1907) ), and to use this finding not only 
in the interpretation of biological observations like those of Hamburger 
but in the explanation of my own water absorption experiments. (Am. 
Jour. Physiol., 20, 330 (1907); Pfliiger's Arch., 124, 69 (1908)). 



BIOLOGICAL APPLICATIONS 



433 



The experimental observations on changes in cell volume 
upon which the just detailed conclusions are based were made 
by Hamburger in 1887, though they were not published until 
1904, because the results did not fit in with the conception of 
the living cell as an osmotic system which Hamburger, like the 
plant physiologists, JH. De Vries and W. Pfeffer, before him, 
was most interested in seeing established experimentally. The 
role of the colloids in accounting for the exceptional behavior of 
these various cells was, however, considered by Hamburger. 
Unfortunately he believed the latter a mere adjunct 1 to the bio- 
logical importance of osmotic pressure, and not, as seems more 
correct, of primary importance — of such importance, in fact, that 
it not only relegates the role of osmotic pressure to a secondary 
place, but in most instances, if not all, questions its entire bio- 
logical significance so far as water absorption is concerned. In a 
much more positive way has Wolfgang Pauli 2 declared the 
swelling of white blood corpuscles in dilute acids and alkalies to 
be analogous to the swelling of colloids under similar conditions. 

Ill 

ON THE INTERPRETATION OF SOME EXPERIMENTS ON 
WATER ABSORPTION BY MUSCLE 

It is well to return at this point to a consideration of certain 
experiments carried out by Jacques Loeb and E. Overton on 
the absorption of water by muscle. While the experimental 
results of the two authors agree very well, their explanations 
of them are very different. As the views of neither have found 
general acceptance on account of the serious objections that can 
be raised against them, I would like to call attention to the har- 
monizing explanation that can be given of the observed facts 
on the basis of the colloid idea of water absorption as already 
discussed in a previous section 3 dealing with the absorption of 
water by muscle. 

1 " Die an der wasseranziehenden Kraft des Zellinhalts wenig betheiligten 
• Colloidtheilchen," Hamburger, Osmotischer Druck und Ionenlehre, 3, 4., 

Wiesbaden (1904). 

2 Wolfgang Pauli: Ergebnisse der Physiologie, 6, 126 and 127 (1907). 

3 See page 151. 



434 



(EDEMA AND NEPHKITIS 



If a frog's muscle is dropped into distilled water it suffers a 
progressive increase in weight. This phenomenon is usually 
interpreted as a response to immersion in a solution of too low 
an osmotic pressure, so that water is absorbed by the cell contents. 
I maintain that this is not correct, for were it, all our muscles 
ought to swell whenever we consume a quantity of fresh or dis- 
tilled water, and a frog living in a fresh-water pond ought to do 
likewise. But this does not occur. Clearly the muscle swells 
only because removed from the body. 

The difference between the muscle inside and outside of the 
body is this: Outside of the body the muscle develops acid, 
and in this and its effects upon the muscle colloids I would find 
the cause for the increased absorption, in distilled water. Added 
to this is the effect of the diffusion of salts out of the muscle, 
for the higher the concentration of salts in a (hydrophilic) pro- 
tein colloid the less does that colloid swell in a dilute acid. Quite 
contrary to the generally accepted belief, a loss of the osmotically 
active electrolytes of a tissue may, therefore, distinctly favor 
the absorption of water. We will do well to consider this when- 
ever w~e try to define wherein lies the " poisonous " effect of 
distilled water. 

That the extirpated muscle develops acid must be borne in 
mind when we try to interpret the effects of acids, alkalies and 
salts upon it. To put a muscle into a dilute acid instead of 
into distilled water is simply to add the effects of the external 
acid to that produced spontaneously by the muscle. The effect 
of putting a muscle into an alkali must depend upon the con- 
centration of the acid formed spontaneously in the muscle and 
the concentration of the added alkali. Depending upon whether 
the latter partially, entirely or more than entirely neutralizes 
the acid formed in the muscle we get as a final result the muscle 
swelling in a dilute acid plus certain -salts, in a neutral solution 
of certain salts, or in an alkaline solution plus certain salts. As 
the amount of acid formed in a muscle is quite variable, and as 
in consequence the possibility arises of many differently concen- 
trated mixtures of acid, salt and alkali, we have no difficulty 
in accounting for the large variation in results obtained when 
extirpated muscles are placed in dilute alkalies. 

Interesting are the effects obtained when muscles are placed 
in solutions of various electrolytes or non-electrolytes. Let it 



BIOLOGICAL APPLICATIONS 



435 



again be recalled that the extirpated muscle develops acid and 
that in consequence its colloids are really absorbing water in a 
medium containing acid as well as the salts or non-electrolytes. 
To consider first the electrolytes. Overton expresses surprise 
that while a 0.6 per cent sodium chlorid solution is in " osmotic " 
equilibrium with the red blood corpuscles of the frog, the muscle 
of the same frog demands a 0.7 per cent solution to keep it from 
swelling. The explanation is found in this: The muscle pro- 
duces acid rapidly (within minutes to hours), while the red blood 
corpuscles do so only very slowly (requiring several hours to days). 
To counteract the earlier accumulation of acid in the muscle 
requires more neutral salt. The sodium chlorid solution that is 
customarily spoken of as a " physiological," " isosmotic " or 
" isotonic " salt solution for use with frogs' muscle is, therefore, 
one that is sufficiently concentrated to just prevent the swelling 
of the muscle through the production of acid that takes place 
within it. When now the " isotonicity " of different salts is 
determined it does not surprise us to find that this is not identical 
with their " isosmoticity," for the physiological coefficient is not 
identical" with the physical one. On the osmotic conception of 
water absorption physically "isosmotic " solutions ought to be 
physiologically " isotonic." Yet experimentally this is not 
found to be the case. On the colloid basis of water absorption 
this result, of course, does not surprise us, for physically isosmotic 
solutions of different salts are not equally effective in reducing 
the amount of water absorbed by a (protein) colloid swelling in 
the presence of a dilute acid. 

With every increase in the concentration of the salt solution 
we expect on the colloid basis a decrease in the amount the muscle 
swells. Experiment shows this to be the case. As we pass from 
the " hypotonic solutions to those considered " isotonic " 
the muscle swells progressively less. If enough salt is added, 
the muscle not only does not swell, but shrinks to less than the 
volume of the freshly extirpated muscle. This marks the pro- 
gression from the " isotonic " solutions to the " hypertonic." 
To explain these facts on the osmotic basis, Overton assumes 
the individual muscle cells to be impermeable to the salt. In 
the colloid theory the cells may be freely permeable, which, 
as a matter of fact, we know physiologically they must ye, other- 
wise it would be impossible to affect the behavior., of muscle as 



436 



(EDEMA AND NEPHRITIS 



markedly as we can experiment ally through various electro- 
lytes. 

Let us now turn to the non-electrolytes. Overton concludes 
that the muscle cells are permeable to practically all these. 
This conclusion, drawn from the fact that a long series of chemical 
compounds permit muscle to swell just as though they were not 
present, is undoubtedly correct, though it is not explained by 
saying that an osmotic membrane exists about the muscle cells 
which excludes salts while it is permeable to these non-electrolytes. 
The extirpated muscle again absorbs water because it develops 
acid when taken out of the body, and non-electrolytes in con- 
trast to the electrolytes are, in the concentrations employed, 
practically without effect in antagonizing the action of the 
acid. These conclusions may be illustrated by citing two of 
Overton's experiments. 

(a) A sartorius muscle which has not changed in weight after 
some hours in a 0.7 per cent NaCl solution undergoes no change 
in weight if placed in a solution of 0.7 per cent NaCl contain- 
ing 5 per cent methyl alcohol, in spite of the fact that the osmotic 
pressure of this mixture is equal to a 5.2 per cent NaCl solution. 

Overton explains these facts by saying that in a solution 
of 0.7 per cent NaCl, the osmotic pressure within and without 
the cells is the same, and that while the osmotic pressure of the 
second solution is vastly higher than that of the contents of the 
muscle cell, it cannot become effective and withdraw water from 
the cell, because the methyl alcohol enters almost instantly into 
the muscle fibers. The correct explanation to my mind is this: 
The sodium chlorid solution has a concentration just sufficient 
to counteract the effect of the acid formed in the excised muscle, 
and so maintains the colloids of the tissues in a condition in 
which their capacity for holding water suffers no great change 
in the hours devoted to the experiment. As the non-electrolytes 
are practically without effect upon this, an addition of 5 per 
cent methyl alcohol to the pure sodium chlorid solution does 
not alter this absorption of water by the muscle. 

(b) A sartorius muscle which is placed in a solution of 0.5 
per cent NaCl plus 3 per cent methyl alcohol — a solution which 
has approximately the osmotic pressure of a 3.6 per cent NaCl 
solution — gains in weight just as though it had been placed in 
a pure 0.5 per cent (a somewhat hypotonic) NaCl solution. If 



BIOLOGICAL APPLICATIONS 



437 



removed to a 0.7 per cent NaCl solution, the original weight is 
regained. 

Our explanation of these facts reads as follows: The muscle 
gains in the NaCl-methyl alcohol mixture because the concentra- 
tion of the NaCl is too low to keep the colloids of the tissues from 
swelling in consequence of the acid produced in the muscle after 
removal from the body, and so it absorbs water. The presence 
of the methyl alcohol is without effect because the non-electro- 
lytes are practically without effect on the swelling of colloids in 
the presence of an acid. When the muscle is removed to the 
0.7 per cent NaCl solution a concentration is encountered which 
counteracts the effect of the acid more completely, and since 
the taking up and giving off of water by colloids represent in 
large measure reversible processes, the muscle gives up some 
of its absorbed water and so assumes its original weight. 

It is a simple matter, therefore, to account for the available 
experimental facts on the absorption of water by muscle on the 
colloid basis. Not only are the facts which it has been difficult 
to harmonize with the osmotic conception of water absorption 
explained in this way, but all the phenomena which we have been 
most willing to accept as osmotic may well represent only a 
fraction of that greater series of phenomena which we have 
designated as colloid. The question of whether the laws of 
osmotic pressure are at all applicable to the biochemistry of 
water absorption is therefore raised in the special case of muscle 
as it was previously raised in the case of spermatozoa, isolated 
epithelial cells, and white blood corpuscles. 

That the laws of osmotic pressure, even as rendered more 
generally applicable to biological material through Overton's 
special assumptions, are incapable of accounting for all the ob- 
served biological phenomena, is admitted by this author himself, 
and in seeking an explanation of various aberrant phenomena he too 
considers the role of the tissue colloids. He refers, as did Pfeffer 
before him, to the part played by the imbibition water of the cells 
(Quellungswasser) , and at one point, correctly to my mind, declares 
the swelling of muscle in dilute acids to be identical with the swell- 
ing of fibrin in dilute acids. But upon this colloid absorption he 
does not lay much weight, as is evident even in his latest writings. 1 

1 See, for example, his article in Nagel's Handbuch der Physiologie, 2, 2te 
Halfte, 744 to 896, Braunschweig (1907). 



438 



(EDEMA AND NEPHRITIS 



It must be clearly understood that this questioning of the role 
of osmotic pressure in biological material so far as water absorp- 
tion is concerned does not question its importance in the general 
problem of the diffusion of dissolved substances. This is an 
entirely separate problem. The advantage of the colloid concep- 
tion of water absorption is that it permits of the diffusion of 
dissolved substances into regions where on the osmotic concep- 
tion they could never get. As already pointed out, neither do 
my views affect or tend to minimize in the slightest the great 
biological significance of the law of partition as worked out by 
Hans Meyer and E. Overton in their experimental studies 
on the cell lipoids. 

IV 

ON THE NATURE OF HEMOLYSIS 1 

The important place which the teachings of colloid-chemistry 
find in the analysis of such a problem as that of hemolysis is 
indicated in these paragraphs. The commonest methods now 
known by which hemolysis (an escape of hemoglobin from the 
red blood corpuscles) may be brought about may be summed up 
thus: 

(a) Through the addition of water to the blood, or through 
immersion of the red blood corpuscles in any salt solution hav- 
ing a concentration below a certain value (as ordinarily stated, 
below the osmotic concentration of the plasma). 

(6) Through the addition of alkalies. 

(c) Through the addition of acids. 

(d) Through the addition of urea and certain other simple 
chemicals such as alcohol, acetone, and most ammonium salts. 

• Most ammonium salts allow hemolysis to occur even when 
present in concentrations at which other salts do not permit it. 

(e) Through putrefaction of the blood. 

(/) Through electricity, but only under circumstances which 
allow of the formation of acids and alkalies in the solutions con- 
taining the corpuscles. This paragraph, therefore, constitutes 
only a subheading of b and c. 

(g) Through heating the blood. 

1 Martin H. Fischer: Kolloid-Zeitschr., 5, 146 (1909). 



BIOLOGICAL APPLICATIONS 



439 



(h) Through the addition of complex chemical substances, 
such as saponin, sapotoxin, bile derivatives, and snake venom. 
With these we must class the specific thermolabile hemolysins. 

While hemolysis is easily produced by any of the methods 
outlined, the following difference is to be observed between the 
various methods. When a specific hemolysin, or a poison capable 
of acting at a very low concentration, is added to the blood, 
the hemoglobin escapes from the corpuscle, . but the corpuscle 
undergoes no change in size. With few exceptions this is not 
the case in any of the other solutions — in all- of them the red 
blood corpuscles increase in size when the concentration at 
which hemolysis occurs is reached. Especially marked is this 
increase in size in solutions of acids and alkalies in which he- 
molysis occurs very rapidly, and in which swelling is most pro- 
nounced. 

It is not strange, therefore, that a causal connection has 
been sought between this escape of hemoglobin and the swelling 
of the corpuscle. In nearly all of the illustrations given, the 
two processes go hand in hand — it is generally stated that as 
soon as the red blood corpuscle swells it gives up its hemoglobin. 
It is not surprising in consequence that to several observers 
it should have seemed as though the only thing necessary for a 
complete understanding of the physical (not biological) half 
of this problem of hemolysis was a physico-chemical concep- 
tion of the process of swelling. 

Close study revealed that the salt solutions which just pre- 
vent the hemolysis of red blood corpuscles all have very nearly 
the same osmotic pressure, and so we find the theory advanced 
that the red blood corpuscles are surrounded by a semipermeable 
film, and that they swell or shrink, give up their hemoglobin 
or do not do so, depending upon whether the surrounding solu- 
tion has a lower osmotic concentration than the corpuscular 
contents or the reverse. This conception is a purely mechanical 
one — as soon as the osmotic concentration of the fluid without 
the cell is below that of the cell contents, water passes into the 
cell, which in consequence swells. When this swelling has become 
sufficiently great, the corpuscle is rent asunder and the hemo- 
globin escapes. 

As the number of experimental observations on the behavior 
of the red blood corpuscles- has increased, more and more facts 



440 



CEDEMA AND NEPHRITIS 



have come to light which show that the laws of osmotic pressure, 
so far as this swelling is concerned, have only a most limited 
application to the problem of hemolysis, if any. 1 It is needless 
to recite all the objections here. 

By way of illustration, it is enough to mention that isosmotic 
solutions of all salts and non-electrolytes do not at a certain 
concentration prevent hemolysis (ammonium salts, for example); 
that the amount of swelling of red blood corpuscles in isosmotic 
solutions of different salts and non-electrolytes is not the same; 
and that with the same salt the calculated decrease or increase 
in the volume of the corpuscle is not strictly proportional to the 
increase or decrease in the osmotic concentration of the surround- 
ing medium. Certain of these objections have been met, at 
least in part, through Ovekton and Meyer's studies on the 
lipoids. But even with the modifications introduced by these 
and other workers many of the phenomena observed, notably 
the action of acids or alkalies, cannot be at all explained on 
the osmotic basis. 

If we call to mind once more the effect of various external 
conditions on the swelling of protein colloids, a ready explanation 
is obtained of most of the phenomena observed in hemolysis so 
far as the changes in the size of the corpuscles is concerned. Red 
blood corpuscles (or more correctly put, their stromas) swell 
most in solutions of acids or alkalies. This is also true of protein. 
The presence of various salts diminishes the amount that red 
blood corpuscles swell. The same is true of protein. Doubling 
the osmotic concentration of the salt does not halve the volume 
of the protein — the volume remains greater than half the original. 
Red blood corpuscles behave similarly. When isosmotic solu- 
tions are compared, red blood corpuscles are found to swell 
more in some than in others. We found the same to be true 
of protein. All these analogies seem to me to indicate that 
the changes in the volume of the red blood corpuscles are dependent 
primarily upon changes in their colloids. 2 Those external condi- 

1 See for example the careful studies of Hans Koeppe: Arch. f. (Anat. u.) 
Physiol., 162 (1895); Pfliiger's Arch., 62, 573 (1896). 

2 Wolfgang Pauli, Ergebnisse der Physiologie, 6, 127 (1907), seems first 
to have considered it possible that the absorption of water by colloids and 
the absorption of water by red blood corpuscles are analogous. He does not 
discuss the matter of loss of color. More recently Julius Kiss (Das perio- 
dische System der Elemente und Giftwirkung, Vienna (1909), only accessible as 



BIOLOGICAL APPLICATIONS 



441 



Hons which increase the capacity of the colloids for holding water 
cause red blood corpuscles to swell, and those which do the reverse, 
cause them to shrink. 

It will be noticed that I have limited myself thus far to a 
discussion of the swelling and the shrinking of the red blood 
corpuscle, and have connected these processes in no synonymous 
way with the escape of hemoglobin from the stroma. This is 
because / consider changes in the volume of the red blood corpuscles 
and the loss of hemoglobin by the stroma separate processes, which 
while they may often be associated, have really nothing to do with 
each other. This conclusion is based upon the following facts: 

When we attempt to construct a red blood corpuscle mentally, 
these points are of interest: The red blood corpuscle is essentially 
a mixture of several colloids. Of first interest is the protein 
body which is ordinarily said to constitute the stroma and which, 
from the way it becomes gelatinous in agglutination experiments, 
has been described as " fibrin-like " in character. Every one of 
its physico-chemical reactions betray it to be a hydrophilic colloid. 
Mixed with this stroma are the two lipoids, lecithin and cholesterim 
According to R. Hobee, the former of these particularly shows 
some of the pronounced reactions of the hydrophilic colloids (as 
witness its so-called "myelin reaction"). These two fat-like 
bodies have, however, a property not possessed by the protein 
portion of the corpuscle — they are good solvents for ether, chloro- 
form, alcohol, and the remaining lipoid-soluble substances. A 
fourth important constituent of the red blood corpuscle is the 
hemoglobin. This, too, is colloid, even though most of the hem- 
oglobins can be obtained with varying ease in crystalline form. A 
class difference, however, exists between hemoglobin and the other 
colloids enumerated as contained in the red blood corpuscle. 
Hemoglobin is not a hydrophilic, but a hydrophobic colloid; it is 
not a so-called emulsion colloid (emulsoid) as the protein constitu- 
ents of the red blood corpuscle, or lecithin, but a suspension colloid 
(suspensqid). 

What now is the nature of the combination between the various 
hydrophilic colloids (the stroma with the lecithin and cholesterin 
mixed in) and this colored "suspension" colloid? Hemoglobin 
cannot simply be dissolved in the red blood corpuscle, for the 

a book review) comes to the same conclusion. Kiss, however, seems to con- 
sider swelling and loss of hemoglobin parallel processes. See above, 



442 



OEDEMA AND NEPHRITIS 



amount present is entirely too high. Neither can it be held in 
the corpuscle because this is covered by a semipermeable mem- 
brane. For reasons touched upon in discussing the biological 
significance of the analogy between the swelling of hydrophilic 
colloids and of protoplasm such a conception of the living cell 
is impossible. Nor is this membrane notion tenable in the mod- 
ified form according to which it is made up of lipoids. The 
hemoglobin is contained in no such oil-covered sac. to flow out 
whenever this is dissolved or punctured. The hemoglobin must 
be combined in some more or less fixed way with the rest of the cor- 
puscle. The lack of evidence to show that this combination between 
stroma and hemoglobin is a chemical one, and the fact that an 
enormous amount of hemoglobin is held by a very small amount of 
stroma 1 leads me to assume that the combination between the 
hemoglobin and the rest of the corpuscle represents an adsorption 
phenomenon. 2 

To test this hypothesis I constructed a system which simulated 
red blood corpuscles and tried the effect of different external con- 
ditions upon it. I used powdered fibrin stained deeply red with 
neutral carmine. This combination was chosen in order to obtain 
a hydrophilic colloid (fibrin) united with a hydrophobic colloid 
(carmine). 3 

As many, if not most, of the dyeing processes represent just 
such combinations between colloids, it would, of course, be an 
easy matter to choose other hydrophihc colloids, and other dyes, 
and depending upon their general and their specific properties, 
obtain results similar to and different from those which I obtained 
with my carmine-stained fibrin. I found, for example, that 
fibrin stained with hematoxylin behaves much like that stained 
with carmine. 

The fibrin is stained by placing it in a beaker and covering it 
with a carmine solution. It is interesting to see how the fibrin 
absorbs enormous amounts of the dye. One has to add fresh 

1 Red blood corpuscles contain from 35 to 45 per cent solids, of which 
from 80 to almost 95 per cent Tin man) consists of hemoglobin. 

2 See page 210. As generally held, this adsorption is a purely physical 
combination dependent upon the enormous surface presented by the adsorbing 
material. T. Brailsford Robertsox has recently criticised this view and 
insisted that the combination might be chemical. It does not matter, so far 
as our argument is concerned, how this discussion is finally settled. 

3 My carmine solution was readily precipitated by salts,, and was analyzable 
under the ultra-microscope. 



BIOLOGICAL APPLICATIONS 



443 



dye time after time to replace that which the fibrin has taken 
up from the supernatant liquid. 

The retention and loss of color by this carmine-stained fibrin 
is very similar to, and occurs under the same conditions as, the 
retention and loss of hemoglobin by the red blood corpuscle. This 
is readily apparent on comparing the following paragraphs with 
the similarly lettered ones given earlier in this section : 

(a) If the red-stained fibrin is placed in water, the water slowly 
becomes red. In a solution of sodium chlorid, or in the chlorids, 
bromids, acetates and sulphates of sodium, potassium or lithium, 
this loss of color does not occur until after two or more days, when 
the supernatant liquid may become faintly pink. 

(6 and c) If a little of any acid or alkali is added to the colored 
fibrin, whether suspended in distilled water or in a solution of 
sodium chlorid, the loss of color occurs promptly. While the 
colored and powdered fibrin when suspended in salt solution 
has an opaque appearance, the bright transparency of a blood 
that has been laked is suggested after the carmine has come out. 
Upon standing for a little while the fibrin flakes sink to the bottom 
of the test-tube, so that the clear, transparent, red solution collects 
above the swollen uncolored " shadows " of the fibrin particles. 

(d) Urea at any concentration brings about a prompt loss of 
color by the carmine-stained fibrin. Ethyl and methyl alcohol 
or glycerin act similarly, but not so powerfully. Solutions of 
ammonium salts also allow the stained fibrin to lose color in a 
way that the other salts do not. 1 

(e) I allowed some carmine-stained fibrin to putrefy in an 
uncovered dish. As the putrefaction progressed the supernatant 
liquid became more and more red. 

(/) The effect of electricity was not studied. 

(g) Gently heating some carmine-stained fibrin brings about 
a prompt loss of color. 

(h) The effect of such substances as saponin, snake venom, 
etc., has not yet been studied. 

The way in which red blood corpuscles lose their hemoglobin 
is not unlike the manner in which carmine-stained fibrin loses 

1 It is, of course, to be foreseen that were the carmine dissolved or adsorbed 
in a lipoid, the effect of the ethyl and methyl alcohols would be much more 
marked, and so imitate the phenomena observed in hemolysis yet more 
perfectly. 



444 



(EDEMA AND NEPHRITIS 



its red color in a dilute alkali. As is well known, red blood cor- 
puscles when subjected to a hemolytic agent do not lose their 
coloring matter suddenly, but progressively. When ordinary 
blood is mixed with water the hemoglobin ring above the sedi- 
mented corpuscles slowly grows a deeper and deeper red. The 
same occurs with colored fibrin. In this simple fact is found 
a serious argument against any of the generally accepted mechan- 
ical conceptions of hemolysis which only postulate ruptured 
membranes and the escape of the hemoglobin contained within 
these membranes. Were the idea correct the escape of hemo- 
globin would always have to occur more or less suddenly, while 
we know it to be, as a matter of fact, a progressive affair. 

Just as it has been found that an escape of hemoglobin and 
a change in the size of the red blood corpuscle (the stroma), while 
frequently associated, do not quantitatively parallel each other, 
so also can carmine-stained fibrin be made to lose or retain its 
red color entirely independently of the amount of change in the 
volume of the fibrin particles. The red fibrin swells enormously 
and promptly loses its color in a dilute alkali. The higher the 
concentration of the alkali the more rapidly and completely does 
the fibrin lose its color, yet so far as the swelling of the fibrin 
is concerned an optimal point is reached beyond which every 
increase in the concentration of the alkali only makes for a dimin- 
ished absorption of water. Again, if a little ammonium chlorid 
is first added to the alkali, the loss of color is (practically) unaf- 
fected, and yet the fibrin swells but little. In other words, the 
swelling of the colored fibrin follows the laws which Gertrude 
Moore and I have previously laid down ; the loss of color entirely 
different ones. 

It seems to me that this analogy between the loss of hemo- 
globin by the red blood corpuscles and the loss of color by carmine- 
stained fibrin is more than accidental, and lends no mean support 
to the contention that the combination between hemoglobin and 
stroma is an adsorption phenomenon. If this view is accepted, 
then henceforth we will have to look for an interpretation of the 
phenomena of hemolysis into a different chapter of physical 
chemistry than that into which we have been accustomed to look. 

Instead of fibrin and carmine, as already pointed out, any 
other hydrophilic colloid united with any other of the ordinary 
(colloid) dyes might just as well have been chosen. The majority 



BIOLOGICAL APPLICATIONS 



445 



of these dyeing processes represent adsorption phenomena. We 
have also learned how these adsorptions may be increased, 
decreased or prevented altogether, as witness our use of the most 
varied mordants, precipitants, fixants and bleaches. Many of 
the methods thus employed (as the use of salts, acids, bases, 
formaldehyd, colloids of various kinds, heat, electricity, etc.) 
have a parallel in the ways and means by which the combination 
between hemoglobin and stroma may be increased or decreased. 1 
The relationships between the different colloids in the case of 
the red blood corpuscles are, of course, much more complicated 
than in the case of carmine-colored fibrin. In place of only two 
colloids, we have in the red blood corpuscle at least four, and 
this makes for an infinitely more complicated system. Not only 
may the adsorption characteristics of the individuals of a group 
of colloids toward any one other (hemoglobin in this case) be 
different, but they may mutually affect each other and so alter 
each other's adsorption characteristics. Lecithin and cholesterin, 
for example, have properties which allow them not only to share 
in, or modify the ordinary adsorption phenomena, as exhibited 
by the protein constituents of the red blood corpuscles, but 
because of their lipoid character they may not only absorb sub- 
stances which the rest of the corpuscle cannot take up, but they 
may be affected by means which do not affect the rest of the blood 
corpuscle. Just in so far as these lipoids affect the relationship 
of hemoglobin to the protein constituents, or of hemoglobin to 
themselves, any substance capable of affecting the lipoids (chloro- 
form, ether, acetone, etc.), must be able to influence the whole 
problem of the relation of the hemoglobin to the rest of the blood 
corpuscle, and so the problem of hemolysis. 

1 Oscar Berghausen showed me in Paul G. Woolley's laboratory in 
the University of Cincinnati, an excellent illustration of this. The hemolysis 
of human red blood corpuscles by carbonic acid can be markedly inhibited 
or prevented entirely by the addition of various salts. This explains why 
administration of properly selected salts (calcium salts and alkaline salts) 
tends to inhibit or stop the periodic destructions of the red blood corpuscles 
in paroxysmal hemoglobinuria, while the presence of acids (as after exposure 
to cold, compression of the blood supply, etc.) precipitates such attacks. 



446 



(EDEMA AND NEPHRITIS 



V 

ON GROWTH AND SOME GROWTH PHENOMENA 

The turgor of plant and animal cells is generally recognized 
as of such fundamental importance in growth and some of its 
associated phenomena, that the following remarks, which are 
intended to show how important a role the colloids may play in 
the whole problem, are perhaps not out of order. 

Let us first consider the question of growth in general. As 
the term has been given various meanings by different authors 
during the past half century, it is well that we begin with a defi- 
nition. Least open to objection is that of T. H. Huxley, who 
speaks of growth as " increase in size." C. B. Davenport defines 
it more precisely when he regards it as " increase in volume." 
Objections to all other definitions arise from the fact that in them 
are too often included those changes which are better considered 
under the caption " differentiation." These changes, while they 
may serve as a necessary introduction to, accompaniment of, 
or consequence of growth, have really nothing to do with the 
process itself. Driesch's distinction between a " passive " growth 
due simply to the taking up of water and an " active " growth 
due to assimilation is excellent, though, as Davenport has 
pointed out, the term "passive " is poorly chosen, for the taking 
up of water is by no means a passive process, and that part of 
growth in which water is absorbed usually gives far more pal- 
pable external evidence of its existence than that included under 
Driesch's heading of " active " growth. 1 

An objection that we might raise against Huxley and Daven- 
port's definition arises from the fact that not every increase in 
the volume of a cell, a tissue or an individual necessarily repre- 
sents what is ordinarily regarded as growth. The development 
of an oedema in the extremities of an individual, the temporary 
swelling of a muscle after exercise, the imbibition of water by 
certain cells of the sensitive plant when touched, would all, 
according to Huxley and Davenport, have to be regarded as 
" growth." In actual practice we would, of course, have little 
difficulty in distinguishing between true growth and the phe- 

1 See C. B. Davenport: Experimental Morphology, 281 to 375, New 
York (1908). 



BIOLOGICAL APPLICATIONS 



447 



nomena cited. What seems interesting to me is that in the end, 
when the physical analysis of these various physiological and 
pathological processes is complete, I believe we will find that 
what makes these processes overlap in definition makes them 
overlap in nature also. 

The question to which anyone discussing the general problem 
of growth (increase in volume) is most desirous of getting an 
answer is this: What is the source of the energy for growth? That 
the energy set free is at times exceedingly great is clearly enough 
indicated by the every-day evidence of the enormous pressures 
exerted by the growing tips of roots and stems, and the direct 
measurements that have been made of the pressures exerted by 
woods, pulps and seeds when soaked in water. The greatest 
osmotic pressures that may be conceived in cells (assuming them, 
for example, to contain saturated solutions of substances of very 
low molecular weight) cannot account for more than a fraction 
of the observed pressures. The pressures exerted by swelling 
colloids constitute an adequate source. We need only to say how 
under the conditions in nature these pressures are rendered 
effective. 

Let it first be called to mind that an absolute sine qua non 
for growth is the presence of water. How necessary is an ade- 
quate supply is evidenced by the farmer's worry about rain, 
and the laboratory experience of every worker in physiological 
botany. Secondly, all growth in volume is preceded by the 
production of various hydrophilic colloids. But not . only are 
various colloids produced, but conditions which particularly favor 
the absorption of water by these colloids are also instituted. 
It is the rule, for example, that the growing tips of plants 
contain much acid. Many of them are sour to the taste and 
will even turn congo-red, blue. The role of acids in making 
various protein colloids swell is familiar to us from previous 
considerations. We have no difficulty now in understanding 
the observation long familiar to the plant physiologists (to 
whom we are indebted for most of our knowledge of growth) 
that there exist in the tips of plants three well-defined regions 
of growth. 1 At the extreme tip is found a region of rapid 
cell division with comparatively slow growth. Here is occurring 
a deposition of colloid material. Below this is found a region 

x See Davenport: Experimental Morphology, 283, New York (1908). 



448 



(EDEMA AND NEPHRITIS 



exhibiting great growth In this but little increase in colloid 
material is noted, but the greatest absorption of water. Why 
such a process should be found to consume much less time than 
the synthesis of colloid material in the tip explains itself. The 
third region again shows little or no increase in volume, but 
abounds in the changes collectively termed " differentiation." 
In plant cells a part of this differentiation consists in the forma- 
tion of cellulose walls. As cellulose constitutes a colloid that is 
not affected by acids, bases, salts and various non-electrolytes 
at concentrations compatible with life, changes in the volume 
of adult cells (such as growth phenomena) are impossible. Only 
the colloid material within the cellulose membrane can be affected 
by these substances, in consequence of which it may shrink away 
from the cellulose membrane (plasmolysis) or swell to burst it 
(plasmoptysis). 

The colloid conception of water absorption also gives us 
the means of understanding the mechanism of certain growth 
curvatures and curvatures due to tropisms of various kinds as 
manifested in plants and animals. The remarks that' follow 
apply particularly to plants, in which Sachs first worked out the 
general problem of the tropisms, though they are just as applicable 
to many animals whose tropisms Loeb has shown to be identical 
with those demonstrated by Sachs in plants. 

In consequence of the directive action of various external 
stimuli (light, heat, chemicals, electricity, water) the growing 
parts of plants bend and grow toward or away from the source 
of the stimulus (positive and negative tropisms) . Growth curva- 
tures may also evidence themselves in consequence of differences 
in the intensity of the action of external stimuli. Various explana- 
tions have been given of how these curvatures are brought about. 
In most the effect of an increased growth, as evidenced particularly 
through the presence of an increased amount of water in the convex 
portion of the plant stem or root, or the animal organism, over 
that of the convex portion, best explains the observed phenom- 
enon. The question at issue now is how such an increased 
absorption of water by one side of a stem, for example, is brought 
about. Osmotic forces have been considered, but they are in- 
adequate from both a qualitative and a quantitative standpoint. 
The phenomenon is quite easily understood on the basis of the 
absorption of water by colloids. We know, first of all, that 



BIOLOGICAL APPLICATIONS 



449 



tropic curvatures both in plants and in animals are confined 
almost entirely to the actively growing parts, and of these, par- 
ticularly to those regions in which various hydrophilic colloids are 
being produced most energetically (as in the tips of roots and 
stems where synthetic changes are most active). We know 
further, from the experimental studies of F. Czapek, 1 that under 
the "stimulus" of a tropism the chemistry of the stimulated 
protoplasm becomes entirely different from that of the unstim- 
ulated. Between these chemical differences, the hydrophilic 
colloids and an available source of water all the conditions are 
offered which lead to inequality in the swelling of the two 
sides of the vegetable or animal organism, with a consequent 
turning toward or away from the source of the stimulus. It 
also becomes intelligible why the older portions of a plant usually 
take no part in these tropic curvatures. The cells constituting 
them are surrounded by a (colloid) framework (such as cellulose) 
which is not affected by the slight chemical changes (low con- 
centrations of acids, alkalies and variations in the distribution 
of various salts) that are capable of affecting so markedly the gen- 
eral body of younger cells and the cell contents of the older ones. 2 
Through these more or less rigid cell walls both the expansion 
and the contraction of the adult cell is markedly hindered. < 
Our remarks show that in the last analysis various external 
stimuli produce their effects through chemical changes which 
they induce in the growing protoplasm. The effects of these 
external conditions come, therefore, to be referred to just such 
local chemical differences which we have long recognized as 
underlying the local irregularities in growth originating within 
the plant or animal itself. How important in this problem 
must be the production in different parts of the growing organ- 
ism of different colloids (albumin, glycogen, starch, cellulose, 
lipoids, with their qualitative and quantitative differences in 
their capacity for holding water) or, with the same colloid, the 
localized production of acids, alkalies and salts is readily apparent. 
We can also see why, barring specific chemical effects, the action 
of electrolytes on growth should be so much greater than that 

*F. Czapek; Ber, d, deut, Bot. Gesellsch., 15, 516 (1898). 

2 See, for example, the experiments of Louis Kahlenberg and Rodney 
True: Botanical Gazette, 22, 81 (1896), on the effects of acids, alkalies and 
salts on growth. 



450 



(EDEMA AND NEPHRITIS 



of non-electrolytes. Electrodes affect colloids in comparatively 
low concentrations, while most of the non-electrolytes do not. 1 

These ideas on growth can be tested and many of its phe- 
nomena mimicked in the laboratory with a few conoids and 
various electrolytes and non-electrolytes. What must happen 
in these experiments- can very naturally be foreseen, though the 
results are nevertheless interesting. With the use of cylinders, 
strips and leaves of gelatin various phenomena considered charac- 
teristic of the tropisms resulting from the action of chemicals, 
light, heat, etc., and certain irregularities in growth resulting from 
internal causes can easily be imitated in the laboratory. When 
such gelatin preparations are painted with a little acid on one 
side and are then dipped in water, beautiful negative curvatures 
are produced. If acidified gelatin is used and one side is painted 
with an alkali or a neutral salt, positive curvatures result. Or 
if a mixture of gelatin with egg albumin is employed a negative 
curvature results when a weak acid is employed, while a positive 
results if a stronger one (nitric acid) or a salt capable of coagulating 
the albumin is applied. When any dry acid (tartaric, oxalic) is 
stirred into gelatin in an irregular way and strips are then cut out 
of it and moistened with water, complicated curvatures, spirals 
and other irregularities in growth, such as characterize flowers, 
for example, can easily be obtained. 

In conclusion, let attention be called to the ready explanation 
which the colloid conception of water absorption offers of the 
ways and means by which certain plants and animals protect 
themselves from loss of water. Aside from certain gross advan- 
tages of external form, protective covering, etc., it is known 
that plants possess internal mechanisms by which they protect 
themselves from loss when water becomes scarce. It is such 
mechanisms that enable the plants of the deserts and the dunes 
to maintain their existence. Certain aquatic strains of animal 

1 These colloid-chemical views on growth have found valuable support 
and development in the papers of K. Gedroiz (Russ. Journ. f. exp. Land- 
wirtsch., 11, 66 (1910)) and G. A. Borowikow (Biochem. Zeitschr., 48, 230 
(1913); ibid., 50, 119 (1913) which show that the absorption of water by 
plants and their growth is governed by the laws controlling water absorption 
in simple colloids. More recent verification of the principles here laid down 
is found in the studies of D. T. MacDougal and his co-workers: Science, 
41, 502 (1916); ibid., 46, 269 (1917); Proc. Soc. Exp. Biol, and Med., 15, 
58 (1917); ibid., 16, 33 (1918); Proc. Am. Philos. Soc, 56, 289 (1917); 
Hydration and Growth, Washington (1920), 



BIOLOGICAL APPLICATIONS 



451 



and vegetable life are also possessed of such mechanisms, other- 
wise they could not withstand transference from fresh water to 
sea water, and vice versa. Through the work of van Ryssel- 
berghe 1 we have learned that when water is scarce certain 
plants convert some of their starch into oxalic acid. Those 
types of plants which under natural conditions are most liable 
to suffer from lack of water (the succulents) seem all to possess 
the interesting property of reducing their output of carbon 
dioxid, while producing at the same time various organic acids 
as soon as subjected to unfavorable conditions for growth. 2 These 
phenomena of acid production have generally been interpreted 
as meaning that by such methods the plant increases the number 
of soluble molecules in its cell contents and so increases its osmotic 
pressure. A more correct explanation, it seems to me, is this — 
through the production of these acids the capacity of the plant 
colloids for holding water is increased, so that the agencies operat- 
ing to rob it of this water are counteracted. A question that 
awaits an answer, in the case of animals is whether a like produc- 
tion of acids is responsible here also for the maintenance of a 
normal water content, as when a fish, for example, born in fresh 
water moves out to sea. 

The important help that the absorption of water by colloids 
can render the general problem of the ways and means by which 
the movement of sap can be accomplished and maintained, in 
trees for example, needs no specific comment. 

VI 

ON THE CONTRACTION OF CATGUT AND THE NATURE 
OF MUSCLE CONTRACTION 3 

The problem of muscular contraction naturally divides 
itself into three parts — a study of the physical, changes that 

1 Quoted by Hober: Physikalische Chemie d. Zelle u. d. Gewebe, 2d Ed., 
63, Leipzig (1906). 

2 Another means of protection against water loss resides in the conversion 
of crystalloid material into hydrophilic colloids, or colloids having a low water 
holding capacity into such as have a higher one. A splendid discovery in 
this direction is that of D. T. MacDougal and H. A. Spoehr (Year Book 
17, Carnegie Institution, 85 (1918)) who found the leaves of desert plants 
to reduce their polysaccharids to pentosans (mucilages) as water was with- 
drawn from them. 

3 William H. Strietmann and Martin H. Fischer: Kolloid-Zeitschr., 
10, 65 (1912); Lancet-Clinic, 108, 205 (1912), 



452 



(EDEMA AND NEPHRITIS 



characterize the muscular contraction, a study of the chemical 
changes that underlie this phenomenon, and lastly, that which 
is usually regarded as the most important part of the whole, 
the means by which the chemical energy regarded as the source 
of the muscular contration is converted into the mechanical. 
The physical changes of muscular contraction have by all odds 
received the greatest amount of study; next in order stand the 
chemical. Least agreement exists at the present time in the 
matter of how the chemical changes lead to the mechanical. 
It is more particularly toward the solution of this phase of the 
problem that these paragraphs are intended to contribute. 
What we have to say is best begun by detailing the results of a 
few experiments on the contraction of catgut. 

1. Observations on the Contraction of Catgut 

(1) As is well known since the classical studies of T. W. 
Engelmann, 1 it is possible to make raw catgut undergo alternately 
a marked shortening and an elongation by changing the char- 
acter of the surroundings in which the catgut is placed. Engel- 
mann found that catgut suspended in water shortened greatly 
when the water was heated, to lengthen once more when this 
was subsequently cooled. The following experiments show 
how such alternate contractions and relaxations may be brought 
about by other changes in the surroundings of the catgut, 

(2) We prepared the catgut used in our studies from the com- 
mercial raw catgut sold to surgeons, or from violin strings, the 
material employed by Engelmann. The catgut strings were 
soaked in distilled water before being used, after which they 
were split into as thin strands as possible. One such strand may 
be used for an experiment, but, in order to get greater con- 
tractile force, it is best to use several, as shown in Fig. 132. 
Here four strands of catgut of uniform diameter have been fas- 
tened to the glass rod. It is best to wrap the glass rod with 
silk thread in order to keep the strands from slipping. The 
four strands are then gathered together at the bottom with a 
silk thread and the whole is fitted into a muscle lever such as 
physiologists use, arranged to write on a recording drum. The 
whole is set up in such a way as to make it possible to bathe 

1 T. W. Engelmann: Pfluger's Arch., 7, 155 (1873); Ueber den Ursprung 
der Muskelkraft, Leipzig (1893). 



BIOLOGICAL APPLICATIONS 



453 



the catgut strands with any desired solution without in any way 
disturbing the apparatus, as indicated in Fig. 133. 

(3) When a single strand of catgut, or a set arranged as 
described, has been permitted to absorb as much water as it will 
by being kept in distilled water (or in a "physiological" salt 
solution) no change occurs in the catgut, as evidenced by any 
movement of. the lever, over long periods of time. The point 
of the lever writes a straight line. If we remove the beaker 
holding the distilled water and substitute for it another contain- 
ing a dilute acid of some kind (lactic or hydrochloric is best) 
it is noticed that after a slight latent period the strands begin 




Figure 132. 



Figure 133. 



to contract and the lever point writes a a curve as shown in Fig. 
134, I. After obtaining a maximal amount of shortening, a 
horizontal line is written as long as the catgut remains in the acid 
solution. If this is now taken away (indicated by the right- 



454 



(EDEMA AND NEPHRITIS 



hand arrow in Fig. 134 and the distilled water is replaced, the 
lever point begins to fall, and slowly returns to its old base- 
line level. 

The height of the contraction is dependent in an interesting 
way upon the strength of the acid solution. Curve I of Fig. 
134 was obtained by passing from distilled water to n/40 
hydrochloric acid and then back to distilled water. Curve II 
was obtained in an identical way with n 60 hydrochloric acid, 
and Curve III with n 80 acid. These curves indicate that the 
greater the concentration of the acid, the higher the contraction. 
To this there is, however, an upper limit, n/40 hydrochloric 
acid representing very nearly the optimal one for the contrac- 




Miautes 



Figure 134. 

tion of catgut strands. Curve IV, which is the lowest of the 
series in Fig. 134, was obtained with n/20 hydrochloric acid. 

(4) The state of the catgut is of importance in determining 
the height of the contraction. Freshly soaked catgut gives the 
highest contractions. If the catgut is allowed to remain in dis- 
tilled water for several days, the height of the contraction as 
obtained with a given concentration of acid becomes progressively 
less. This is shown in Fig. 135, where are recorded the con- 
traction curves obtained with -the same strands of catgut used 




iMrnutes 



Figure 135. 

to produce Fig. 134, after they had been kept in water for five 
days. As the recording lever, the weight carried, etc., were the 
same in both series of experiments, the two sets of curves may be 
compared with each other directly. Curves I, II, and III 
in Fig. 135 were obtained with the same concentrations of hydro- 
chloric acid as those similarly marked in Fig. 134. What is the 



BIOLOGICAL APPLICATIONS 



455 



nature of the changes in the catgut induced by prolonged immer- 
sion in distilled water we are not prepared to say, although we 
are most inclined to think them due to the digestion of the protein 
material, catalyzed in part no doubt by the ferments derived 
from the bacteria which get into the vessels holding the catgut 
in our ordinary laboratory experiments. 

(5) Fig. 136 shows the effect of the thickness of the catgut 
strand upon the contraction. In this experiment only single 
strands of the same length could, of course, be used. The con- 
centration of acid employed was n/40 hydrochloric in each case; 
c indicates the curve obtained with the thickest fiber, a that 
with the thinnest. It is readily apparent that the contraction 
occurs the more rapidly the thinner the fiber. Curve a is not 
as high as the other two. As the weight lifted was the same 
with all three fibers, such a result is easily accounted for on the 
basis of the relatively greater stretching force applied to the 
fiber in the case of a than in the case of the other two. 




t 

Minutes ' ~ 1 ' 1 ' 

Figure 136. 

(6) We noted above that catgut strands relax entirely when 
the acid solution in which they have contracted is replaced by 
distilled water. To get a complete relaxation, however, takes 
a long time. In other words, the fiber maintains a residuum 
of contraction. What this amounts to, after repeated transitions 
of the catgut from water to acid and back to water, is indicated 
in Fig. 137. On the first passing from water (base line) into 
n/40 hydrochloric acid the maximal contraction indicated by 
the first rise of the line is obtained. This is a 
record taken on a still drum. The first hori- 
zontal plateau records the maximal contraction, 
made by rotating the drum slightly forward. 
The fall in the record obtained on changing to 
water fails to reach the original base line. On 




456 



(EDEMA AND NEPHRITIS 



again passing to acid the second rise is obtained, which it will be 
noted is higher than the first contraction. The second fall on 
immersion in water does not even reach the low point previously 
attained, and so on for a series as indicated in the figure. Then for 
a long period the contractions and relaxations remain equal, and 
there are no appreciable changes in the levels of the maximal and 
minimal points attained. But if the series of changes from acid 
into water and back again were kept up long enough, it is clear that 
the maximal points attained would become progressively lower 
and the amount of residual contraction diminish, due to changes 
suffered by the catgut (digestion?). Justification for such a 
conclusion is found in the differences observable in the contrac- 
tion curves obtained from fresh and old catgut (Figs. 134 and 
135). 

(7) In Fig. 138 is shown the effect of adding various amounts 
of a neutral salt upon the contraction of catgut in an acid solu- 
tion. Curve I shows the contraction of a series of strands when 
immersed in n/50 hydrochloric acid. The moment of immersion 
is indicated by the arrow a. At c the acid is replaced by water 
and relaxation results. Curve II was obtained by immersing 
the catgut at the point a, not in a pure acid, but in one containing 
in addition 0.25 per cent sodium chlorid, at the point b in a 
pure 0.25 per cent sodium chlorid solution, the relaxation 
occurring as indicated. Curves III, IV, V and VI were obtained 
in identical fashion by alternate immersion of the catgut in 
n/40 normal hydrochloric acid containing respectively 0.5, 
0.75, 1.0 and 3.0 per cent sodium chlorid, and then in 0.5, 0.75, 

I. and 3.0 per cent pure sodium chlorid. In Curve VI it will 
be noted that the power of the acid in bringing about a contrac- 
tion has been suppressed entirely. As a matter of fact the fibers 
have contracted even less than in pure water (the curve lies 
slightly below the base line). 

(8) The series of curves in Fig. 139 show an extremely interest- 
ing contrast to those of Fig. 110. Curve I is again a contraction 
followed by a relaxation as obtained by alternate immersion of 
the catgut in n/50 hydrochloric acid and in pure water. Curves 

II, III, IV, V, and VI were obtained by immersion in acid of 
the same concentration, but the solutions contained in addition 
respectively 0.25, 0.5, 0.75, 1.0 and 5.0 per cent sodium chlorid. 
At points lying between the arrows b and c, these solutions 



BIOLOGICAL APPLICATIONS 



457 




458 



(EDEMA AND NEPHRITIS 



were replaced by pure water. In every case further contrac- 
tion is obtained before the relaxation sets in, which occurred 
immediately in Fig. 138 when we passed to salt solutions instead 
of pure water. 

Results identical with those portrayed in Figs. 138 and 139 
are obtained if any other acid (such as lactic) is used in place of 
the hydrochloric acid, or any other salt (such as sodium lactate) 
takes the place of the sodium chlorid. Neither is it necessary 
that the salt and the acid used have a common ion. Any salt 
will depress the contractions obtainable in any acid provided 
they do not react chemically with each other to undergo double 
decomposition. 




.'Minutes 1 1 1 

Figure 140. 



(9) In Fig. 140 the facts already noted in Fig. 139 are brought 
out in a slightly different way. In the first portion of the curve 
is noted the contraction obtained in a pure acid solution. Between 
the two points marked Ringer solution the catgut strands were 
immersed in this solution, after which water was substituted for 
it. As is readily apparent, one obtains under such circumstances 
a second contraction which is practically as high as that obtained 
initially. 




2 'Minutes' ™ 1 1 ~ r 

Figure 141. 



(10) In Fig. 141 is shown the effect of immersion in suc- 
cessively greater concentrations of the same acid. In passing 
from one to the other a greater and greater contraction is obtained 
until a maximal one is reached in the highest (optimal) concen- 
tration of the acid. 

(11) Thus far the relaxations of the catgut after immersion 



BIOLOGICAL APPLICATIONS 



459 



in an acid have been obtained by using either water or a neutral 
salt. The relaxation occurs much more rapidly and the base 
line is regained sooner if for the neutral salt is substituted one 
that has the power of combining with the acid used to induce the 
contraction. The effect of this is shown in Fig. 142. In this 
case the contraction was obtained in n/2 hydrochloric acid, 
the relaxation in m/5 sodium bicarbonate solution. 

2. Interpretation of Experimental Findings 

It requires no imagination to see in Fig. 142 a duplicate of 
the tracing obtained when ordinary striated muscle is made to 
contract. But before we discuss this further let us see with what 
general phenomena in colloid chemistry we may correlate the 
above described experimental results. 1 

Catgut chemically considered is a protein, and its general 
physico-chemical reactions betray its colloid character. The 
fact that it swells in water at 
once serves to class it with the 
lyophilic colloids, or, as water is 
the absorbed substance, with the 
hydrophilic colloids. Merely super- 
ficial examination suffices, there- 
fore, to place catgut in a group with f JH^^H 

gelatin, fibrin, gluten and serum K 'Minutes 1 
albumin. But it behaves like Figure 142. 

these protein colloids in various 

other directions also. When we observe that on immersion in 
a dilute acid the catgut fiber contracts, we note at the same time 
that it does this by a process of swelling; it becomes thicker and 
shorter. The same thing is noted in the case of gelatin, 
fibrin, gluten or serum albumin. Gelatin, fibrin or gluten swell 
more in any dilute acid than in pure water, and the viscosity of 
serum albumin rises when acid is added to it. If the acid is 
washed out of these colloids, they resume their original form, as 
does the catgut when water replaces the acid solution. Just as gela- 
tin, fibrin and gluten show within certain limits an increase in the 
amount of swelling with every increase in the concentration of the 
acid surrounding them, so also do we note an increased height of 

1 See page 61, 




460 



(EDEMA AND NEPHRITIS 



contraction in catgut when the acid concentration surrounding 
this increases. 

The fact that catgut does not at once return to a previous 
state when the conditions about it are changed has its analog in 
the way in which fibrin, gelatin, etc., only slowly recover from 
the effects of a previous surrounding, when a new one is substi- 
tuted for it (hysteresis). 

With a given concentration of acid, the amount of swelling 
attained by gelatin, fibrin, gluten or serum albumin is reduced by 
the presence of any salt (even neutral salts, and such having no ion 
in common with the acid), and this reduction in the swelling is 
the greater, the stronger the concentration of the added salt. 
The parallel of this is found in the reduction of the height of 
the contraction of catgut in any acid solution, when any salt is 
added, the reduction being the greater the higher the concentra- 
tion of the added salt. When fibrin has been allowed to swell 
to its maximum in a mixture of any acid with a salt, and is then 
placed in pure water, an initial increased swelling of the fibrin 
is noted, before the decrease sets in which brings the fibrin back 
to the degree of swelling characteristic of immersion in pure 
water. It is as though the acid were united more firmly to the 
protein colloid than are the salts. In spite of the greater diffusion 
velocity of acids over salts, the salts nevertheless seem to get out 
of colloid proteins more rapidly than do the acids, an observa- 
tion not without biological importance, nor without interest for 
the theory of the colloid state. This behavior of fibrin also 
has its analogue in the already observed characteristics in the 
contraction of catgut when changed from a salt-acid mixture to 
pure water. . 

Point for point, therefore, the contraction and relaxation of 
catgut (the absorption and secretion of water by catgut) is identical 
with the taking up and giving off of water by various other colloid 
proteins. 

It is easily seen how these experiments on catgut contractions 
correlate themselves with the experiments of Engelmann. What 
happens is identical in both instances, namely, an absorption 
and secretion of water by the proteins composing the catgut, 
only while Engelmann used an increase in temperature to make 
the catgut swell, we used, for purposes that will become evident 
immediately, various acids. 



BIOLOGICAL APPLICATIONS 



461 



3. On the Analogy between the Described Contractions of Catgut 
and the Contraction of Striated Muscle 

It is easily seen how similar are many of the curves illustrating 
these pages with the curves obtained and familiar to every physi- 
ologist when striated muscle contracts. 

Fig. 142 could easily be mistaken for the record of an ordinary 
muscle twitch. In Fig. 141 we observe a series of successively 
higher contractions that remind us of the result when a series of 
inadequate stimuli are thrown at proper intervals into a striated 
muscle. Fig. 140 illustrates a phenomenon of rigor in catgut 
that Edwad B. Meigs has described in muscle. If a frog's 
muscle is immersed in a weak acid it goes into a state of contin- 
ued contraction; if it is then placed in Ringer solution it relaxes, 
to contract a second time if it is subsequently placed in water. 

The series of curves shown in Fig. 138 (and the first half of 
the curves of Fig. 139) illustrate in catgut what is called fatigue in 
striated muscle. The last half of the curves of Fig. 139 show again 
the contractions obtained in moving from an acid solution contain- 
ing salt, into pure water as already referred to in Fig. 140. Fig. 137 
illustrates the staircase phenomenon familiar from muscle physi- 
ology. Not only are the successive contractions of the catgut 
fiber progressively higher, but the fiber does not relax perfectly; 
there remains the residual contraction or increased tone familiar 
to us from muscle preparations. Fig. 136 shows how a catgut 
fibril may remain continuously contracted (tetanus). When we 
compare Figs. 134 and 135, and note how the same catgut fiber 
undergoes changes in its state which alter markedly its power 
to contract under given conditions, we recognize the analog of 
the importance of the state of the muscle in our physiological 
experiments as determining the character of its contraction. 

The question now arises whether these physical analogies 
between the contraction curves written by muscle, and those 
written by catgut strings as described above constitute merely a 
happy coincidence, or whether the two processes are really in 
essence the same; in other words, is the contraction of striated 
muscle' a simple problem in colloid chemistry just as we found 
the contraction of catgut to be? This is our belief. The aniso- 
tropic substance of the muscle corresponds to the catgut threads; 



462. 



(EDEMA AND NEPHRITIS 



the isotropic substance or sarcoplasm to the water that surrounds 
the catgut threads. 

But does our analogy between the contraction process in 
catgut and in muscle extend beyond these physical likenesses; in 
other words, are the chemical surroundings that we used to make 
catgut contract, identical with those that make striated muscle 
contract? This, we think, is also the case. In fact, we sur- 
rounded our catgut with the very chemical conditions which our 
present-day physiology holds to exist in muscle in the various 
phases of its contraction. 

That a muscle produces acid during an ordinary contraction 
constitutes one of the classic facts of our physiology. " This state- 
ment has only recently been generalized to the extent of saying 
that whenever a muscle is found to contract, evidence of acid 
production' in the muscle exists. The contraction of rigor mortis 
is associated with the production of acid in the muscle, a fact 
which made L. Hermann, in calling attention to the analogies 
that exist between the contraction of muscle in rigor mortis and 
the ordinary muscle contraction, venture the suggestion that the 
ordinary single twitch was due to a temporary production of 
acid. More recently, particularly through the work of Fletcher, 
Hopkins and Meigs, it has been shown that in water rigor, heat 
rigor, chloroform rigor, etc., the contractions noted are also always 
associated with the production of acid in the muscle. 

But not only is the production of acid associated with every 
contraction of muscle, it is the cause of this, as has been shown 
particularly well by McDougall and Meigs. McDougall 
studied the effects of acids and various other substances on the 
length of the isolated contractile elements of insect-wing muscle. 
He found these to shorten whenever he brought them in contact 
with any very dilute acid. With increasing concentration of the 
acid he found that an optimum was reached, beyond which a 
lessened contraction was observable. It will be recalled that we 
described the same phenomenon in catgut. When the muscle 
elements were removed from the acid solution to pure water, 
relaxation . set in. The relaxation occurred more rapidly if 
instead of being placed in distilled water the muscle elements 
were placed in a sodium chlorid solution. The more highly 
concentrated this was the more rapidly did the relaxation set in. 
These facts also have their analogs in catgut. 



BIOLOGICAL APPLICATIONS 



463 



Meigs has greatly amplified the experimental observations 
of McDougall and described practically identical findings in 
frog's muscle. 

From these remarks it is clear that the chemical conditions 
which we described above as effective in producing and modi- 
fying the contraction of catgut are identical with those which 
do the same in striated muscle, wherefore we conclude that the 
phenomenon of contraction in muscle is entirely a problem in colloid 
chemistry. If this conclusion is justified, then let us review 
briefly some of our current theories of muscular contraction with 
an eye to discovering which of them are most nearly correct. 
In so doing we shall find that the proponents of these theories 
erred not so much through a failure to recognize that muscular 
contraction represented a colloid problem, but rather in that they 
did not consider this explanation adequate or capable of account- 
ing for more than a small part of the essential phenomena of 
contraction. 



4. Historical and Critical Remarks 

For the first great step toward the formulation of a colloid 
theory of contraction we are indebted to Fkanz Hofmeister, 1 
that old master who has done so much to establish the biological 
importance of the colloid state. Hofmeister built upon the 
fact that protoplasm consists of a series of bodies which are capa- 
ble of imbibing water, and pointed out how in the processes under- 
lying the phenomena of imbibition a migration of water and 
the approximation of two points (contraction) that are sur- 
rounded by envelopes of water must occur whenever the imbibi- 
tion capacity of the one is increased at the cost of the other. In 
this way he tried to account for all the special types of proto- 
plasmic contraction as observed in different animal and plant 
forms. 

The missing element in Hofmeister' s theory — which he him- 
self points out — is that he could not explain why the colloids 
suffered the changes which make for the contraction; in other 
words, the nature of the chemical changes that induced the phys- 

1 F. Hofmeister: Die Lehre von der Pflanzenzelle, Leipzig (1867). Not 
accessible in the original. 



464 (EDEMA AND NEPHRITIS 



ical. For a first suggestion in this direction we are indebted 
to T. W. Engelmann. 1 

Engelmann started from the well-known fact that during 
muscular contraction the carbohydrates and fats disappear from 
the muscle, while carbon dioxid, water, etc., appear in their 
place. This chemical change is associated with the liberation of 
heat, and this fact Engelmann utilized to construct upon it his 
thermodynamic theory of muscular contraction. Briefly formu- 
lated, Engelmann believes that the muscular contraction is 
initiated by a chemical change in the carbohydrates (and fats) 
of the muscle which results in the liberation of heat; this heat 
acting upon the contractile, elements contained in the muscle 
(the anisotropic substance) makes them absorb the isotropic 
substance and so sv T ell and shorten. The physical half of this 
theory, it will be noted, is also an imbibition theory of the nature 
of Hofmeister's. To support this contention, Engelmann 
devisedTiis now famous experiment in which he showed how cat- 
gut — which is also anisotropic — contracts in water when its tem- 
perature is raised, to relax again when the temperature falls. If 
the catgut strand is only momentarily heated, a contraction 
curve is obtained which is identical in appearance with a single 
muscle twitch. 

Engelmann' s theory has been attacked on many sides, to our 
minds often with scant justice when the substituted theories are 
weighed in the balance against his. The best argument against 
it are furnished by two facts: First, the amount of heat produced 
during an ordinary muscular contraction is not sufficient to make 
anisotropic substance, of the nature of that found in muscle, 
shorten enough to explain a muscular contraction. Second, a 
contraction of muscle occurs under circumstances in which there 
may be no production of heat whatsoever. But even after all this 
is granted, the great fact remains that Engelmann was the first 
to create a satisfactory model of the muscular contraction out 
of materials which may be subjected to physico-chemical analysis, 
and so to remove the whole problem from a realm of speculation 
and terminology into one of reason and fact. As will be evident 
later, even in the matter of making a change in temperature 
responsible for the physical phenomena of contraction, he was 

1 T. W. Engelmann: See reference on page 452. 



BIOLOGICAL APPLICATIONS 



465 



not entirely wrong; he only failed to pick the most powerful 
explosive out of a series lying before him. 

The work of L. Hermann constitutes a valuable contribution 
to the establishment of a colloid theory of muscle contraction in 
several directions. Hermann emphasized very clearly the many 
analogies both from a chemical and a physical standpoint that exist 
between the ordinary muscular contraction and the various rigors. 
As " coagulation " is an obvious sign in the rigors, the question of 
whether the ordinary muscular contraction is a " temporary 
coagulation, or a kind of coagulation/' has often been argued 
since Hermann's writings. Hermann took the signs of coagu- 
lation and the contraction of muscle in rigor to represent evi- 
dences of one and the same process, and believed both of them to 
be due to the formation of acid in the muscle which occurs in all 
the rigors. In such a belief he was in part right, -in part wrong. 
In making the production of acid responsible for both he was 
right, but to understand properly what happened beyond this 
point was impossible then, for colloid chemistry had not as yet 
developed sufficiently. 

We know now that the obvious signs of any " coagulation " 
such as that which characterizes the rigors can only be asso- 
ciated with a loss of water by the " coagulated " colloid. 1 As 
the muscular contraction consists of an absorption of water, just 
the reverse of " coagulation/' it is clear that the " coagulation " 
and the contraction observed in muscle in rigor must be entirely 
separate processes. What happens in muscle is identical with the 
development of a clouding in the cornea of an eye simultaneously 
with the swelling of the enucleated eye when this is placed in acid- 
ulated water, 2 or the development of a " cloudy swelling " in any 
of the parenchymatous organs when these are exposed to the same 
conditions. 3 Two colloids at least are involved in the process, and 
while the one is behaving like gelatin, which swells in acidulated 
water, the other behaves like casein, which under the same circum- 
stances is precipitated. In rigor the anisotropic substance swells 
under the influence of the acid and leads to the muscular contraction, 

1 See Wolfgang Pauli: Kolloid-Zeitschr., 7, 241 (1910). Pauli and 
Handovsky: Biochem. Zeitschr., 18, 340 (1910). H. Handovsky: Kolloid- 
Zeitschr., 7, 183, 267 (1910); Fortschritte in der Kolloidchemie der Eiweiss- 
korper, Dresden (1911). Karl Schorr: Cited by Pauli and Handovsky. 

2 See page 806; Martin H. Fischer: Pfliiger's Arch., 127, 40 (1909). 

3 See page 540; Martin H. Fischer: Kolloid-Zeitschr., 8, 159 (1911). 



466 



(EDEMA AND NEPHRITIS 



while under the same circumstances another colloid is being precipi- 
tated (or, to use Hermann's word, " coagulated ") which gives 
the muscle an opaque appearance. As we shall see later, the loss 
of water by the colloid which is being " coagulated " no doubt 
yields that necessary for the swelling (contraction) of the 
other. 

Whether a rigor is reversible or not depends entirely upon 
whether the precipitation of the colloid involved is reversible or 
not; whether, in other words, removal of the condition which has 
made the colloid precipitate permits this to go back into solution. 
Depending upon the means employed to produce the rigor and 
the length of time it has acted, the colloid precipitations may or 
may not be reversible, and so the rigor. 

This matter of rigor can, in a sense, also be mimicked on cat- 
gut. If we allow a chromium salt to act upon the catgut along 
with any acid, then we get not only a shortening of the catgut, but 
a permanent one. 

While maintaining that acid production is responsible for 
the permanent contraction in rigor, Hermann 1 made the further 
valuable suggestion that a temporary production of acid might 
account for the normal muscular contraction. But this remained 
a mere suggestion with Hermann. The idea that the production 
of acid is responsible for the muscular contraction either under 
normal circumstances or in rigor has been particularly clearly 
enunciated by William McDougall. 2 This author holds the 
anisotropic substance (the sarcomeres or contractile elements of 
the muscle) to be built up of tubules " having delicate walls 
and containing a fluid or viscid substance." The contraction he 
holds to be due to an absorption of fluid by these tubules 
" determined by the setting free of lactic acid in the fluid con- 
tents of the sarcomere, aided perhaps by an increase in the 
osmotic equivalent of these fluid contents through an increase 
in the number of molecules in solution. Then so long as the 
acid remains present in the fluid of the sarcomere, the additional 
fluid absorbed will be retained and the state of contraction 
will continue. But as soon as the acid escapes from the sarco- 
mere the additional fluid will also escape with it into the sarcov 
plasm and allow relaxation to take place." 

1 L. Hermann: Hermann's Handbuch der Physiologie, 1, 255 (1879). 
2 William McDougall: Jour. Anat. and Physiol., 32, 187 (1898). 



BIOLOGICAL APPLICATIONS 



467 



With McDougall's description of the histology of striated 
muscle we are not immediately concerned; in passing we would 
only point out that much of the discussion as to whether a histo- 
logical structure is " solid " or " liquid " is purposeless, for animal 
and plant structures are chiefly colloid in composition, and the 
colloids that compose living matter combine in one the properties 
usually cited as characteristic of both the solid (maintenance 
of form) and the liquid state (surface tension, diffusion of dis- 
solved substances). 

It is clear that McDougall's ideas readily permit one to see 
why a single muscle twitch, a tetanus, or a rigor due to death, 
acid or water, all have the phenomenon of contraction in common. 
Underlying all of them is the production of acid in the muscle 
and depending upon whether this acid production is only tem- 
porary or permanent we have either a temporary or a continued 
state of contraction. 

McDougall worked with isolated muscle fibrils. If these are 
placed in a weak solution of any acid (acetic or lactic) they swell 
and shorten. If they are then placed in distilled water and the 
acid is washed out of them they relax again. When the acid 
exceeds a certain optimal concentration the shortening becomes 
less marked. If any salt is present in the dilute solution of the 
acid, the contraction is lessened, or may not appear at all. If 
fibrils that have undergone no marked contraction in a solution 
containing both acid and salt are transferred to pure water, they 
undergo a rapid shortening. We need not re-emphasize that these 
statements are point for point identical with those we made above 
on the contraction and relaxation of catgut under similar circum- 
stances. 

The theoretical views of McDougall have found excellent 
experimental support and have won precision through the careful 
studies of Edward B. Meigs. 1 This author has not only 
collected the evidence which shows that an acid production 
underlies every phenomenon of contraction as observed in 
striated muscle, but he was the first to recognize and clearly 
express the fact that we deal in this problem (in part only, accord- 
ing to Meigs) with a colloid phenomenon, and that the acid 

1 E. B. Meigs: Zeitschr. f. allg. Physiologie, 8,81 (1908); Am. Jour. 
Physiol., 22, 477 (1908); ibid., 26, 191 (1910); Jour. Physiol., 39, 385 
(1909). 



468 



OEDEMA AND NEPHRITIS 



owes its action to the fact that it makes certain colloids of the 
muscle swell. 

Since Meigs' writings McDougall 1 has also expressed this 
idea in unequivocal terms. 

With this colloid view of the muscular contraction we heart- 
ily concur. The criticisms we have to make of McDougall 
and Meigs' ideas are that on both theoretical and experimental 
grounds they do not consider the colloid conception entirely 
adequate. McDougall believes that in the process of con- 
traction osmotic effects play a part in addition to the colloid, 
while Meigs thinks, in his analysis of the nature of water absorp- 
tion by striated muscle, that osmotic phenomena are con- 
cerned here. No experiments are cited by'^McDouGALL to sup- 
port his osmotic hypothesis, and as Meigs, who is the best 
champion of McDougall's ideas, agrees that the swelling of 
the contractile elements in muscle (the essence of contraction) 
is a colloid phenomenon, we may consider it settled that at least 
so far Meigs holds that osmotic phenomena do not play a role. 

In maintaining that the " living " muscle is surrounded 
by osmotic membranes, Meigs calls attention to the curve of 
water absorption exhibited by a muscle immersed in distilled 
water. Such a muscle rapidly attains a maximal swelling, then 
for a period loses in weight, gains in weight a second time, and 
then slowly loses again. 2 The curve representing the second 
gain in weight comes at the same time and accompanies the 
contraction of the striated muscle, and this Meigs is willing to 
accept as a process of colloid swelling (swelling of the contractile 
elements under the influence of an acid). But the first swelling 
Meigs does not consider as of the same type. He here follows 
the older belief of E. Overton, that osmotic membranes exist 
about the " living " muscle cell. 3 When excised and placed 
in distilled water, these osmotic membranes are destroyed, in 
part owing to the accumulation of acid within the muscle, in 
part due to differences in osmotic concentration inside and 
outside the muscle cell which lead to their rupture. When 

1 William McDougall: Quarterly Jour. Exp. Physiol., 3, 53 (1910). 

2 See page 155 of this volume; also Martin H. Fischer: Pfluger's Arch., 
124, 69 (1908). E. B. Meigs: Am. Jour. Physiol., 26, 191 (1910). 

3 The same erroneous view is held by R. Beutner on the basis of experi- 
ments carried out under Jacques Loeb's direction. Biochem. Zeitschr., 
39, 280 (1912). 



BIOLOGICAL APPLICATIONS 



469 



the membranes are thus destroyed, the fluid behind them is 
allowed to escape, and so the muscle loses temporarily in weight. 
But this temporary loss in weight can be interpreted more 
simply as a phenomenon in colloid chemistry. The muscle 
contains several colloids, and the maximal swelling and pre- 
cipitation points for any given set of conditions are not the same 
for all these colloids. Under the influence of an acid, for example, 
the maximal swelling of the one may therefore be attained and 
exceeded sooner than that of another, and so a swelling of one 
colloid in the muscle may have reached and gone beyond its 
maximum (an increase followed by a decrease in weight) before 
another has attained its maximum. As a matter of fact we 
know that just such a relationship must exist between the dif- 
ferent colloids in a striated muscle when, this contracts nor- 
mally. There is no free water in the body; it is all held in com- 
bination with the colloids of the tissues. 1 If one colloid element 
in an organism swells (say the anisotropic substance), it can do 
this only as it first robs some other element of its content of 
water. It would be eminently useful, therefore, if the condi- 
tions which on the one hand make for a swelling of the aniso- 
tropic substance, on the other make for the shrinkage (giving 
up of water) of another (isotropic substance). 

To our mind all that characterizes the phenomena of water 
absorption and of contraction, or the loss of water and of relaxation 
in muscle, together with the various phenomena of " coagulation " 
observed in the rigors, represent but simple expressions of the 
effect of various acids and salts on that mixture of the several 
protein colloids which make up the muscle. We propose shortly 
to deal further with this subject. Here we would only direct 
attention once more to Fig. 140 and the apparently complicated 
series of reactions that may be obtained from a simple catgut 
fibril when exposed to the action of water, acids and salts. It is 
reactions of this type in muscle cells that have given rise to the 
highly complicated beliefs regarding the existence of membranes, 
etc., in and about them. As a matter of fact, we have no more 
reason for postulating their existence in muscle than in our catgut. 

Much of the confusion that exists to-day in this whole prob- 
lem of contraction, water absorption, irritability, etc., as observed 

1 See page 296; also Martin H. Fischer: Kolloidchem. Beihefte, 2, 304 
(1911). 



470 



(EDEMA AND NEPHRITIS 



in muscle, arises from the fact that various authors have too 
carelessly passed from observations made on one to conclusions 
regarding another, instead of studying each phenomenon sepa- 
rately. Association of phenomena does not make them identical. 
Just as we learned that the signs of coagulation observed in rigor 
mortis are not identical with the phenomena of contraction 
observed in the same condition, so also does water absorption 
not parallel loss of irritability, or loss of irritability mean a loss 
of the power of contraction. 

When the original report of these observations on catgut was in 
press, the colloid-chemical theory of muscular contraction upon 
which they bear received valuable and independent support through 
the work of von Furth and Lenk 1 on rigor mortis. In a care- 
ful and convincing study of this problem these authors show 
that the postmortem contraction of muscle is a colloid process 
and influenced by various external conditions in the same way 
and in the same direction as the swelling of proteins. Somewhat 
later Wolfgang Pauli 2 discussed the general problem of muscular 
contraction and in bringing fresh support for the colloid theory 
of contraction further illuminated the subject by a critical dis- 
cussion of the chemical changes which induce the colloid ones. 
Independently of these authors, J. Grober 3 has shown how 
the rate of swelling in simple colloids approximates the rate of 
the muscular contraction and quite recently Rudolf Arnold 4 
has studied the water absorption and the contraction of different 
kinds of human muscle in a way which brings new and corrob- 
orative evidence of their essential colloid-chemical character. 

1 von Furth and Lenk: Biochem. Zeitschr., 33, 341 (1911). 

2 Wolfgang Pauli : Kolloidchemie der Muskelkontraktion, Dresden 
(1912). 

3 J. Grober: Munch, med. Wochenschr., 2433 (1912). 

4 Rudolf Arnold : Kolloidchem. Beihefte, 5, 411 (1914). 



PART SIX 
NEPHRITIS 



\ 



PART SIX 
NEPHRITIS 



I 

THE THESIS 

As apparent to the most casual student, our ideas regard- 
ing the nature and cause of nephritis are to-day in a state of 
chaos. The reasons for this are not far to seek. While physi- 
ology, pathology and clinical medicine have all contributed 
toward the analysis of the problem, little or no effort has been 
made by the various workers in each of these fields to find com- 
mon ground with those in another. Such effort needs to be 
made, for, as pointed out above, we step in no abrupt manner 
from the physiology of the kidney into its pathology, or from 
laboratory findings into the practical problems of everyday 
medicine. 

We need in these pages to get a definition of nephritis which 
is sufficiently broad, and so we shall use this much-abused term 
in its ordinary clinical sense. It becomes therefore a convenient 
heading under which to consider those clinical pictures which 
are characterized by the appearance of casts and albumin in the 
urine; by certain morphological changes in the kidney; by a 
change in the amount of water put out by it; by changes in the 
absolute and relative amounts of dissolved substances given off 
in the urine, and by such associated phenomena as oedema, 
increased blood pressure and cardiac hypertrophy. How these 
all fit together will develop later. 

I need not be reminded that the term nephritis with its 
implied meaning of an inflammation of the kidney is a misnomer, 

473 



474 



(EDEMA AND NEPHRITIS 



because in the u non-purulent inflammations of the kidney" which 
constitute the accepted of the nephritides, the ordinary patho- 
logical evidences of inflammation are largely missing. Termin- 
ological discussions do not change nor yet analyze the well- 
recognized pathological conditions with which we are dealing. 

That which we as clinicians have come to regard as a clinical 
entity, and call nephritis, represents in reality the aggregate of 
a number of changes each of which must be treated separately 
if we would come to a satisfactory understanding of what is 
included under the clinical term. At least silently, the necessity 
for such a division of the subject has, as a matter of fact, long 
been recognized, for have we not largely given up the discussion 
of nephritis and taken up more and more that of albuminuria, 
anuria, cedema, chlorid retention — all of them parts of nephritis? 
Yet the persistence of the term nephritis in spite of our daily 
efforts in medicine to become scientifically more precise seems 
to be not without reason; it is the one term by which we are 
enabled to express the fact that the albuminuria, the anuria, 
etc., nearly always appear as associated phenomena. But from 
such a constancy in association we are enabled to draw an impor- 
tant conclusion — they must all have a common cause. The fol- 
lowing pages attempt to show what this is. 

To render our argument clear, we will at once state our gen- 
eral conclusion: 

All the changes that characterize nephritis are colloid-chemical 
in nature and due to a common cause — the abnormal production 
or accumulation of acid and of substances which in their action 
upon colloids behave like acid, in the cells of the kidney. To the 
action of these upon the colloid structures that make up the kidney 
are due the albuminuria, the specific morphological changes noted 
in the kidneys, the associated production of casts, the quantitative 
variations in the amount of urine secreted, the quantitative varia- 
tions in the amounts of dissolved substances secreted, as well as the 
other signs of nephritis which appear in direct connection with the 
kidney. The alleged consequences of kidney disease such as oedema, 
high blood pressure, uremia, etc., are not consequences, but accom- 
panying signs and symptoms which demand separate discussion 
and analysis. 

We shall now take up the proofs for these contentions in 
order. It is convenient to consider first the chemical factors 



NEPHRITIS 



475 



which bring about the colloid changes, and of these we shall 
lay main stress on the abnormal production or accumulation of 
acid in the kidney. Not only does this seem to be the most 
important, but our remarks concerning it may serve as an out- 
line by which the value of any other factor in the problem may 
subsequently be tested. If our thesis is correct we must be 
able to show that : 

1. There is evidence of an abnormal production or accumula- 
tion of acid in the kidney, or of conditions predisposing thereto 
in every case of nephritis; and conversely that: 

2. Any means which leads to an increased production or 
favors the accumulation of acid in the kidney results in nephritis. 

II 

AN ABNORMAL PRODUCTION OR ACCUMULATION OF ACID 
IN THE KIDNEY OCCURS IN EVERY CASE OF NEPHRITIS 

§1 

If nephritis results whenever the acid content of the kidney 
is sufficiently increased then evidently the maintenance of its 
normal state must be intimately associated with maintenance 
of neutrality in it. We are therefore, first of all, interested in the 
fact that (exclusive of the gastric juice, the urine, and less pos- 
itively, the sweat, vaginal secretion, and alimentary contents 
when fat is. fed) the fluids and tissues composing the normal mammal 
are to all intents and purposes neutral in reaction and are capable 
of maintaining this neutrality against the introduction of con- 
siderable acid into them. 

In the terms of our modern physical chemistry and accepting 
for the time being the generally held notion (to which we do not 
ourselves at all subscribe that cells and body fluids (like 
blood) are "solutions" which may be compared to the dilute 
solutions of the physical chemists, an acid reaction is due to the 
presence of free hydrogen ions, an alkaline reaction to the presence 
of free hydroxyl ions. A neutral reaction means, therefore, one of 
two things: either neither of these ions are present, or else just as 
many of the one as of the other, so that they balance each other. 
1 See pages 52 and 775. 



476 



CEDEMA AND NEPHRITIS 



The claim that the blood is neutral (and from this it has been gen- 
erally assumed that the tissues themselves are also neutral in 
reaction) may at first sight occasion surprise when considered in 
the light of our older teachings that the body fluids and the cells 
are "alkaline." But these older conclusions were based upon 
results obtained with titration methods. The blood, for example, 
was held to be "alkaline," because it is capable of neutralizing 
acid. But the power of a solution to neutralize an acid is not an 
index of its content of free hydroxyl ions which alone the modern 
physical chemists accept as the true measure of its alkalinity. 
Such hydroxyl ion measurements upon the blood (and the tissues) 
were first made by P.Fkaenkel, 1 G.FARKAS, 2 and Rudolf Hober. 3 
The observations of these authors agree in pronouncing the normal 
blood neutral in reaction; as neutral as pure distilled water. 

Of further interest is the fact that this state of neutrality of 
the blood (and of the tissues) is maintained against the introduc- 
tion of considerable acid or alkali into them. When exposed to 
the action of an acid, it is found that the normal hydroxyl ion 
concentration of the blood drops with the progressive introduc- 
tion of acid into it, in the form of a curve, which falls only very 
slowly at first, and then more rapidly. Just why and how the 
state of neutrality is thus maintained does not at this particular 
moment interest us, but it may not be amiss to point out that 
two factors are involved in the process. The first lies in the 
fact that such salts as sodium carbonate and disodium hydrogen 
phosphate are capable of uniting with acids (carbonic and 
phosphoric acids) to form salts having a higher hydrogen con- 
tent (sodium bicarbonate and sodium dihydrogen phosphate), 
but which in their dissociation yield few more hydrogen ions 
than the salts from which they were originally formed and which 
were present in the blood to start with. In other words, there is 
only a slight increase in the concentration of the hydrogen ions 
(increase in hydrogen ion acidity) in spite of the considerable 
introduction of acid into the system. (L. J. Henderson.) 4 

1 P. Fraenkel: Pfluger's Arch., 96, 601 (1903). 

2 G. Farkas: Pfliiger's Arch., 98, 551 (1903); Arch. f. (Anat. und) 
Physiol., Supplement, 517 (1903). 

3 Rudolf Hober: Pfluger's Arch., 81, 522 (1900); 99, 572 (1903). 

4 L. J. Henderson: Am. Jour. Physiol., 15, 257 (1906); 21, 169.(1908); 
21, 427 (1908); Ergebnisse d. Physiologie, 8, 257 (1909), where extensive 
references to the literature will be found. 



NEPHRITIS 



477 



The other and perhaps lesser element for the maintenance 
of neutrality resides in the amphoteric character (that is to say 
their power of combining either with acids or alkalies) of the col- 
loids found in the blood and tissues. The albumins, for example, 
can unite with considerable quantities of acid (or alkali) with- 
out any decided change in their behavior toward indicators. 
The presence of certain colloids in any system will therefore 
serve to delay the increase in the concentration of the hydro- 
gen ions when an acid is added to this system. 1 But let not 
the impression be gained from these remarks that blood or the tis- 
sues are not sensitive to even very minute additions of acid (or 
alkali) to them. Such an increase in the concentration of the car- 
bonic acid as occurs when normal arterial blood becomes venous 
is already sufficient to reduce the hydroxyl ion concentration in 
the latter to one-half that existing in normal arterial blood. How 
profoundly even such a change affects the state of the colloids we 
will have occasion to discuss later. For the present we are con- 
tent with making the point that the blood and (presumably) 
the tissues are neutral in reaction and that they are capable of 
maintaining this neutrality within rather wide limits, even when 
subjected to the action of an acid. 

§ 2 

As modern physico-chemical studies have reduced what we 
formerly regarded as the " alkalinity " of the blood to a point 
where we may call it neutral, so also have they reduced the 
normal "acidity" of the urine from what we used to assume this 
to be. Just as the neutralizing power of the blood for acids is not 
accepted as a true indication of its reaction, so also is the amount 
of alkali with which a given specimen of urine will combine no longer 
accepted as a measure of its true acidity. To gage this properly 
the concentration of the hydrogen ions in it must be determined and 
this was not done until L. von Rhorer 2 and Rudolf Hober 3 

1 J. Sjoquist: Skand. Arch. f. Physiol., 5, 277 (1895). Otto Cohnheim: 
Zeitschr. f. Biol., 33, 489 (1896). K. Spiro and W. Pemsel: Zeitschr. f 
Physiol. Chem., 26, 233 (1898). S. Bugarszky and L. Liebermann: Pflu- 
ger's Arch., 72, 51 (1898). T. B. Robertson: Jour, of Physical Chem., 
11, 542 (1907) ibid., 12, 473 (1908). 

2 L. von Rhorer: Pfluger's Arch., 86, 586 (1901). 

3 Rudolf Hober: Hofmeister's Beitrage, 3, 525 (1903). 



47S 



(EDEMA AND NEPHRITIS 



applied the principle of the gas chain to the physico-chemical 
analysis of the urine. Table CII. taken from Hober. 1 indicates 
what is the concentration of the hydrogen ions in a series of 
normal morning urines. 



TABLE CII 
Normal Urine 



Hydrogen ion aciditv 
(10- 5 -Ch). 


Titration acidity. 


058 


0.046 


0.52 


0.034 


0.50 


0.042 


0.46 


0.069 


0.31 


0.075 



It would support our idea of the cause of nephritis if it could 
be shown that this acidity of the urine increases in conditions 
associated icith the urinary findings characteristic of such kidney 
disease. How strikingly true this is, is clearly evident from the 
analyses of nephritic urines given in Table CHI also taken from 
Hober and made, of course, without thought of using them for 
such purposes as we do here. 



TABLE Cin 
Abnormal Urine 



Hvdrogen ion acidity 

(lO-i-CH). 


Titration acidity. 


Remarks. 


2.34 
1.50 
0.84 
1.10 
2.20 
2.10 
0.56 
0.67 


0.019i 
0.018 1 
.027 [ 
0.020 J 
0.0221 
0.020/ 
0.014 1 
0.050 J 


Interstitial nephritis. 

Acute nephritis. 

Chronic interstitial nephritis. 



As is seen on comparing the two tables, the active acidity 
of the urine of nephritics may be more than four times that of 
the normal urine. But Table CHI already suffices to betray 
another fact. The highest acidities occur in the acute forms of 
nephritis, in other words, in the same forms in which we find most 
albumin, the largest number of casts, the greatest decrease in the 

1 Rudolf Hober: Phvsikalische Chemie d. Zelle u. d Gewebe. 2d Ed., 
158. Leipzig (1906). 



NEPHRITIS 



479 



urinary output, etc. The lowest values are found in the chronic 
interstitial forms, in other words, in the very types in which 
albumin is found in smallest amounts, or at times not at all. 
The degree of the albuminuria and the other evidences of kidney 
disease therefore tend to follow the degree of acidity. We shall 
have occasion to return to this question later. 

Let us now look at the columns in these tables that record 
the titration acidities. It is such determinations that we find 
recorded in large number in clinical studies of nephritis. When 
the individual titration acidities in the above tables are com- 
pared with their corresponding hydrogen ion acidities, it is 
readily apparent that the two values do not even approximately 
parallel each other. What is learned when the titration acidity 
of the urine is determined, is its capacity to neutralize alkali. 
Under otherwise constant conditions it is clear that this titration 
acidity of the urine must grow with every increase in the amount 
of acid in the urine. The uniformly higher titration acidity of the 
urine in nephritis, as shown not only in tables CII and CIII, but 
in the scores that may be found in any of the larger monographs 
on nephritis, becomes further evidence, therefore, in favor of our 
contention that an abnormal production or an abnormal accumulation 
of acid occurs in the kidney when thus affected. 

§ 3 

In the same way that we use the increased capacity of the 
urine for neutralizing alkali as evidence for the presence of 
abnormally large amounts of acid in it (and so in the kidney cells 
from which this comes) , so also may we use the decreased capacity 
of the blood for taking up acid as evidence in the same direction. 
The titration values of the blood, which the earlier clinical 
observers looked upon as indices of its " alkalinity," may be 
drawn upon for evidence to show that in the nephritides there 
exists a decreased power of the blood to neutralize acids. As 
studied particularly by Rudolf von Jaksch, 1 W. H. Rumpf, 2 
E. Peiper 3 and F. Kratjs 4 a decrease in the acid capacity of 

X R. von Jaksch: Zeitschr. f. klin. Medicin, 13, 350 (1887). 
2 W. H. Rumpf: Centralbl. f. klin. Medicin, 12, 441 (1881). 
3 E. Peiper: Virchow's Arch., 116, 337 (1889). 

4 F. Kraus: Zeitschr. f. Heilkunde, 10, 106 (1889); Arch. f. exp. Path. u. 
Pharm., 26, 181 (1889). 



480 



(EDEMA AND NEPHRITIS 



the blood is noted in no conditions more strikingly than in nephritis 
and its oft associated "uremia." 

§ 4 

Our argument thus far has shown that in nephritis there 
is a great increase in the hydrogen ion acidity of the urine, and 
that in both the urine and the blood there occur changes in the 
titration values which clearly indicate that both are holding a 
more than normal amount of acid. Our knowledge of physi- 
cal chemistry (the laws of chemical equilibrium) permits us to 
utilize these facts as evidence indicating that the kidney itself, 
in other words, everything which lies between the urine on the 
one hand and the blood on the other must, under such circum- 
stances, also shows an increased acid content. But it would 
strengthen this view if we could bring more direct proof in 
support of this deduction. It would be well, of course, if we 
could obtain a direct measure of the hydrogen ion concen- 
tration in the kidney. Gas-chain methods are naturally not 
applicable to solid organs, and to apply them to the expressed 
juice of the kidney would be to introduce so many errors into 
the whole prolbem as to render the conclusions valueless. We 
can, however, obtain material help by using indicators. 

Proof of an increase in the amount of acid held by the kidney 
cells in conditions associated with the urinary findings of nephritis 
is furnished by the following facts: 

In 1885 H. Dreser 1 described a series of experiments on 
the excretion of dyes by the kidney which differed from the 
preceding studies of this subject as first made by R. Heiden- 
hain 2 and M. Ntjssbatjm, 3 in that he utilized the results of his 
experiments in an attempt to get an answer to the question as 
to where in the kidney the acid of the urine is secreted. Dreser 
made chief use of acid fuchsin which he injected in 5 to 10 per 
cent solutions (amounts not stated) into the dorsal lymph sacs 
of frogs. This dye has the property of being red in aqueous 
solution only in the presence of an acid; in an alkaline solution 
it becomes practically colorless (yellow). Dreser therefore rea- 
soned that the presence of a red color in any tissue after the in- 

1 H. Dreser: Zeitschr. f. Biol., 21, 41 (1885); ibid., 22, 56 (1886). 
1 R. Heidexhaix: Pfluger's Arch., 9, 1 (1875). 
3 M. Nussbaum: Pfluger's Arch., 16, 141 (1878). 



NEPHRITIS 



481 



jection of this dye into the circulation of an animal was evidence 
of an acid reaction in that tissue. The first fact noted by Dreser 
that is of interest to us is that after a single dose of acid fuchsin 
the urine is found shortly thereafter to become brilliantly red. 
If the kidney from such an animal is examined no stained cells 
are noted anywhere in the kidney. To interpret this fact we would 
have to say that normally the urine is acid in reaction, hut the cells 
of the normal kidney are not. The following may serve to corrobo- 
rate this finding of Dreser: 

Experiment 55. — Three frogs, weighing 35 grams each, are injected, 
respectively, with 0.25, 0.5, and 1.0 cc. of an aqueous 1 per cent acid 
fuchsin solution, into the dorsal lymph sac. All are seen to secrete 
a red-colored urine before being killed. They are killed respectively 
after 1, and 4^ hours. On autopsy, red urine is found in the bladder 
of each animal. The kidneys are not stained. They are rapidly removed 
from the freshly killed animals, frozen with liquid carbon dioxid 
(on a Bardeen freezing microtome, where the gas does not come in con- 
tact with the tissue) and sectioned. The sections are immediately 
transferred to a slide (without being brought in contact with water or 
any other medium except air), covered with a cover slip, and examined 
under the microscope. None of the kidney tissues is seen to be stained. 
To be sure that the freezing plays no part in the findings, a parallel 
series of free-hand sections and crush preparations of the kidneys are 
made. No stained cells are found. 

When the uncolored sections are touched with very dilute acetic 
acid they are seen gradually to assume a pink color. Acid fuchsin is 
therefore present in the kidney tissues, but as cut from the body the 
reaction of this organ is not such as to allow its red color to appear. 
The pink tinge visible in the kidney after being touched with acid includes 
the glomeruli. - 

Experiment 56. — To show that what was said for the frog holds 
also for the mammal, two young rabbits, weighing, respectively, 184 
and 189 grams, received into the ear veins 2 and 4 cc, respectively, 
of a 1 per cent aqueous acid fuchsin solution. At the end of thirty and 
thirty-five minutes, respectively, they were killed by a blow on the 
head and immediately autopsied. Light red urine was found in the 
bladder of the first, deep red urine in that of the second. The appearance 
of the kidneys in both animals was entirely normal, and no dye was 
visible in the kidneys either macroscopically or microscopically. When 
a little very dilute acetic acid was permitted to flow under the cover 
slips, the sections turned uniformly pink. 

Dreser noted no staining of the frog's kidney until he had 
repeated his acid fuchsin injections several times. Then he 



482 



(EDEMA AND NEPHRITIS 



found that the cells of the convoluted and of the straight tubules 
began to stain red. He interpreted this finding by saying that 
from the long-continued effort on the part of these cells to excrete 
the dye, they become fatigued and so some of the dye remains 
behind to be discovered on subsequent section of the kidney. 
From all these facts Dresek concluded that the acid constituents 
of the normal urine are " secreted " by the convoluted tubules, 
and that since the glomeruli and their capsules remain unstained, 
the " urine " coming from these must be " alkaline " in reaction, 
to change to an acid reaction after passing by the convoluted 
tubules. Whether such conclusions are really justified we shall 
have occasion to discuss later. 

No one can quarrel with the simple experimental finding that 
acid fuchsin does not stain the normal kidney, and does do this 
after repeated and long-continued injections. Such staining of 
the kidney Dr'eser still regards as "physiological." Strictly 
speaking, and for reasons that will be apparent as we go on, 
I shall myself regard it as " pathological." What Dreser 
calls the 11 fatigue " of the cells of those portions of the kidney which 
stain after repeated injections of the acid fuchsin, we are perfectly 
safe in regarding as the first evidences of an abnormal acid content 
in these cells, and we may hold that the repeated injection of this 
dye is itself responsible for such a condition. 

Acid fuchsin is a weak acid, and must produce the same effects 
upon the kidney that we know are produced by the injection of 
any other acid. 1 After the injection of acids we note regularly 
all the signs of a nephritis, and that these were not absent in 
Dreser's experiments is clearly evidenced by the " anuria " 
which this author so often noted in his frogs. 

But Dreser 2 describes yet another experiment which shows 
that an abnormal production or storage of acid occurs in the 
kidney in nephritis. The kidne}^ of the frog receives a blood 
supply, it will be remembered, from two sources — through the 
renal artery, as in mammals, and through a sort of portal system 
analogous to that existing in the liver. The blood from both 
these sources mixes to leave the kidney by way of the renal vein. 
Dreser noted that if acid fuchsin is injected into the abdominal 
vein an hour after the renal artery has been tied, the convoluted 
1 See page 489. 

2 H. Dreser: Zeitschr. f. Biol., 21, 53 (1885). 



NEPHRITIS 



483 



tubules stain red. As already pointed out, no such red staining 
• of the cells is noted if the dye is so injected without ligation of 
the renal artery. Dreser interprets his finding in the terms of 
physiology, but that we deal here with a pathological condition 
of the kidney — a nephritis — is betrayed not only by the fact 
noted by Dreser, that kidneys so treated secrete no urine, but 
by the evidence furnished below, 1 that after occlusion of the 
arterial blood supply to the kidney, acid develops in this organ, 
the kidney swells, the water secretion falls and casts and albumin 
appear in the urine. 

Further tinctorial evidence of an abnormal production or 
accumulation of acid in the kidney in nephritis is furnished by 
certain experiments of R. Heidenhain, M. Nussbaum and P. 
Grutzner with sodium indigosulphonate. This -dye behaves 
similarly to acid fuchsin. It is deep blue or indigo in an acid 
solution and yellow in an alkaline one. The somewhat con- 
tradictory conclusions of these authors, based on their studies 
with this dye, are easily put in order if we try to separate those 
of their findings which are pathological from the physiological. 
In my own experiments on rabbits and frogs, I have, first of 
all, never been able to confirm any but the conclusion of Nuss- 
baum, 2 that no part of the normal kidney stains with sodium 
indigosulphonate. This corroborates the finding obtained with 
acid fuchsin — the normal kidney does not contain sufficient acid 
to bring out the blue color. 

Experiment 57. — Four frogs, weighing 30 grams each, are injected 
respectively, with 0.25, 0.5, 1.0, and 0.25 cc. of a 1 per cent aqueous 
sodium indigosulphonate solution into the dorsal lymph sac. Blue 
urine is voided by each of the animals before being killed. After, 
respectively, forty minutes, fifty minutes, seventy minutes, and 3| hours, 
their heads are cut off and they are autopsied. Blue urine is found in 
the bladders of the last three. Macroscopic examination shows no 
color anywhere in the kidneys of these animals, and microscopic examina- 
tion of frozen sections only confirms this fact. 

Experiment 58. — Three rabbits from the same litter, and weigh- 
ing 497, 575, and 447 grams, respectively, receive, respectively, through 
the ear vein, 1, 2, and 5 cc. of a 1 per cent aqueous sodium indigosul- 
phonate solution. They are killed by a blow on the head one hour 
after being injected. Blue urine is found in the bladder of each. This 

1 See pages 267, 498 and 659. 

2 M. Nussbaum: Pfliiger's Arch., 16, 141 (1878). 



484 



(EDEMA AND NEPHRITIS 



is also present in the ureter of the third. The kidneys are entirely 
unstained in the first two, and no color is found anywhere in the frozen 
sections prepared from these kidneys. The kidney of the third animal 
has a mottled blue appearance superficially, and one section shows some 
blue streaks radiating toward the pelvis of the kidney. Frozen sections 
show no dye anywhere in the kidney substance proper. The blue streaks 
are due to dye found in the lumina of a few of the collecting tubules. 

In apparent contradiction to this simple conclusion that the 
normal kidney does not stain with sodium indigosulphonate, 
stand the classical experiments of Heidexhaix, 1 who found 
certain portions of the kidney, notably, again, the convoluted 
tubules, to stain when the " secretion of the urine was sufficiently 
depressed." Heidexhaix brought about the desired reduction 
in the secretion of urine by such procedures as transverse section 
of the spinal cord in the neck. But as he himself noted, this 
produces an enormous fall in blood pressure. Such a fall does 
not, however, leave the kidney in a normal condition — it spells 
not alone an anuria, but an albuminuria and casts, in other words, 
a " nephritis." The staining of the kidney under these circum- 
stances is again evidence of an abnormal -production or accumulation 
of acid in this organ, a conclusion that we shall shortly be able to 
corroborate by entirely different methods. 

Both Heidexhaix and Dreser have laid special stress on 
the fact that the convoluted tubules stain under the conditions 
offered in their experiments, while the glomeruli remain unstained, 
because it is upon this fact chiefly that they (and their followers) 
have based their conclusion that the different parts of the urin- 
iferous tubule in its course from the glomerulus to the pelvis 
of the kidney have different functions. As generally held, these 
different parts are supposed to secrete into (or, according to 
Carl Ludwig, absorb from) the mother urine — the liquor postu- 
lated by TV. Bowman to be separated from the blood in its passage 
through the glomeruli — as this flows down the uriniferous tubules, 
the different substances which serve to characterize the urine. 
I do not myself question the probability that the different por- 
tions of the uriniferous tubules have different functions, but that 
this is so is not proved by these particular experiments. Strictly 
speaking, the findings of Dreser and Heidexhaix only show 

X R. Heidexhaix: Pniiger's Arch., 9, 1 (1875); Hermann's Handbuch d. 
Physiol., 5, 346, Leipzig (1S83). 



NEPHRITIS 



485 



that, under the conditions of their experiments, the neutrality mechan- 
ism existing in the convoluted tubules is broken down more easily 
than that existing, for example, in the glomeruli. That this approxi- 
mates more nearly a correct interpretation of the observed phe- 
nomena is, as a matter of fact, indicated by the following: 

By simply continuing the conditions which were mentioned 
as effective in leading to a staining of the convoluted tubules, we 
get a staining of the glomeruli. Evidence for the correctness of 
this conclusion can be adduced even from some cursory experi- 
ments mentioned by Heidenhain and Grutzner. As pointed 
out above, the conditions which lead to a staining of certain 
portions of the kidney with acid fuchsin or sodium indigosulpho- 
nate (excessive acid injection, ligation of renal artery, gross falls 
in blood pressure) are conditions which we can show by other 
means to be such as are associated with an abnormal production 
or accumulation of acid in the kidney. No matter how we inter- 
fere with a proper blood supply to the kidney we get such a pro- 
duction of acid. It does not, therefore, surprise us that when 
Grutzner 1 produced circulatory disturbances in the kidney 
by injecting gum arabic, he noted not only the development of 
anuria and albuminuria, but found at the same time that the 
glomeruli and their capsules now stained with sodium indigo- 
sulphonate. Quite as simply can we interpret Heidenhain's 2 
finding that the glomerular tufts stain w T ith sodium indigosul- 
phonate when the ureters are ligated. When this is done the 
urine is dammed back and accumulates in the space between 
the glomerular tuft and the parietal layer of the capsule, in con- 
sequence of which the capillaries composing the tuft are com- 
pressed, so that the normal circulation of blood cannot now occur 
through them. Under these circumstances an abnormal pro- 
duction or accumulation of acid in the cells of the glomerulus 
and the capsule is rendered possible and so the tissues making 
up these structures now stain. 

One can further test the soundness of the reasoning detailed 
here that a staining of the kidney as a whole or in part marks 
the presence of an abnormally high acid content by working 
with excised kidney. Slices of fresh kidney kept in dilute solu- 

1 P. Grutzner: Pfliiger's Arch., 24, 461 (1882). 

2 R. Heidenhain: Hermann's Handbuch d. Physiol., 5, 372, Leipzig, 
(1883). 



486 



(EDEMA AND NEPHRITIS 



tions of sodium indigosulphonate or acid fuchsin stain only very 
slowly and very slightly. But let a trace of acid be added 
and all parts of the section may be made to stain a deep blue 
in a few minutes. In the same way a section of tissue from a 
kidney that has been dead some time (and so contains post- 
mortem acids) stains readily, and. let it be noted, in all its parts. 

It will be recalled by anyone familiar with such studies as 
those of Heidexhaix, Dreser or the numerous investigators 
who since their day have adopted similar experimental methods, 
that these studies are intended to throw light on the problem 
of secretion by the kidney cells. This process of secretion is. 
of course, a dynamic one, made up of two parts, the one concerned 
with the taking up from the blood of the substance to be secreted, 
the other with the giving off of this same substance in the urine. 
The problems involved here are discussed in detail later, but it 
may not be amiss to point out even now that what is so often 
done, namely, the regarding of a mere staining of some or all of 
the cells of an organ as dependable evidence indicating that the 
dye is " secreted " by these cells, is entirely wrong. The presence 
of a dye in a cell does not mean this; nor when cells stain unequally 
does it mean that those most deeply stained are most involved 
in this process. It may mean just the reverse. The staining of 
the excised kidneys described above shows this very clearly. A 
kidney touched with a little acid, or one showing postmortem 
change, stains better than a normal kidney, and this without any 
hope of subsequently u secreting " the absorbed dye. Again, a 
kidney rendered ;i nephritic " by ligation of its arterial blood 
supply stains better than a normal one, and yet no one would 
maintain that a nephritic kidney " secretes " all dissolved sub- 
stances better than a healthy one. 

What really happens in the excised kidneys, or in the " neph- 
ritic " kidneys contained in the still living animal, represents 
but an isolated expression of the general laws that we to-day 
know to underlie all that is comprised in the physical chemistry 
of the process of dyeing. The kidney cells in the experiments 
that have been detailed are stained for the same reason, and their 
staining reactions mean the same thing, as when any ordinary 
lyophilic colloid such as fibrin or gelatin takes up acid fuchsin or 
sodium indigosulphonate. If these colloids are seen to be stained 
red or blue, it means that they contain, under the conditions of 



NEPHRITIS 



487 



the experiment, a certain minimum of acid. But with a given 
concentration of the dye the depth of the staining becomes a 
measure of the acid content, for a given colloid will absorb 
the more of any so-called " acid stain " the higher the con- 
centration of the acid in the colloid. Other things being equal, 
the kidney cells must stain the more intensely with acid fuchsin 
or sodium indigosulphonate, the higher the acid concentration 
developed in them. To this whole question we shall have to 
return later. 

§5 

Yet other lines of evidence may be adduced to prove that in 
nephritis there is an abnormal production or accumulation of 
acid in the kidney. To some of these we return later. 1 

When the carnivorous animal (including man) is subjected 
to intoxication with acid, it meets this to begin with, by neutraliz- 
ing the acid with the fixed bases of its body. But when these 
are heavily drawn upon the organism has a reserve mechanism 
which enables it still further to tolerate an acid intoxication — 
it converts an increasing amount of its protein material into 
ammonia and uses this to neutralize the acid. The high relative 
and absolute ammonia excretion so common in many of the 
nephritides or in patients likely to show albumin and casts in the 
urine with a diminished water output, as in starvation, after the 
anesthesias, after poisoning with phosphorus, arsenic, lead, 
etc., becomes evidence, therefore, of the -existence of abnormally 
great amounts of acid in them. (Munzer, Palma, Araki, Badt, 
Laub, etc.) 

The low carbonic acid content of their blood is further proof 
in the same direction. 2 When any of the fixed acids are introduced 
into the body, or are produced there (lactic, diacetic, betaoxy- 
butyric, abnormally large amounts of sulphuric, phosphoric, 
etc.), either in the course of normal or deranged metabolism 
these tend to drive off the volatile carbonic acid from the blood 
exactly as in test-tube experiments. The low carbonic acid con- 
tent of the blood so common in nephritis and in many of the 

1 See page 778. 

2 See H. Meyer: Arch. f. exp. Path. u. Pharm., 14, 313 (1881); 17, 304 
(1883). See also Lewis, Ryfpel, Wolf, Cotton, Evans and Barcroft: 
Heart, 5, 45 (1913); Jour. Physiol., 46, 53 (1913); Yandell Henderson: 
Jour. Am. Med. Assoc., 63, 318 (1914). 



488 



(EDEMA AND NEPHRITIS 



intoxications accompanied by casts, albumin, etc., in the urine 
is explained in this way. 

Quite recently interesting colloid-chemical evidence of an 
abnormal production or accumulation of acid in the body in 
nephritis has been brought by F. von Hoefft. 1 The coagu- 
lation temperature of proteins is reduced, their alcohol precipi- 
tability and electrical conductivity increased whenever their acid 
content is raised. 2 The blood of patients with nephritis shows 
all these changes. 

The work of A. W. Sellards 3 on the tolerance of patients 
to administration of alkali (sodium bicarbonate) before they 
react to the point of secreting a neutral urine is also of interest 
here. While normal individuals require some 5 to 10 grams, 
patients with recognized " acidoses/' produced by feeding acid 
or in diabetes, were found to need more than these amounts 
(30 grams) before their urines turned neutral. Sellards pro- 
poses the use of such alkali feeding by way of settling whether 
the " nephropathies " are due to " acidosis." Without question- 
ing the justice of Sellards' classification of his patients — for 
as I have insisted it is most important to know whether all of 
a kidney is diseased or only pieces in it — he finds that five of his 
thirteen cases showed a normal tolerance while in all the rest 
it was increased. In one patient he did not get neutral urine 
even after injecting 60 grams of sodium bicarbonate intraven- 
ously, and in a second the urine was still acid after 130 grams. 
Sellards' work has frequently been quoted as evidence against 
my views, but if I am any judge, it is simply a way of saying 
backwards that there is evidence of an abnormal production or 
accumulation of acid in the body in nephritis. 

Ill 

ANY MEANS WHICH LEADS TO AN INCREASED PRODUC- 
TION OR ACCUMULATION OF ACID IN THE KIDNEY IS 
A MEANS OF PRODUCING NEPHRITIS 

We are now ready to discuss the converse of what has gone 
before, and so try to show that any means by which we can bring 

*F. vox Hoefft: Kolloid-Zeitschr., 13, 278 (1913). 

2 See page 147. 

3 A. W. Sellards: Johns Hopkins Hosp. Bull., 23, 289 (1912); ibid., 26, 
141 (1914). 



NEPHRITIS 



489 



about an abnormal production or accumulation of acid in the kidney 
constitutes a method of producing the signs of nephritis. 



1 



The simplest way of increasing the acid content of the kidney- 
consists, of course, in the introduc- 
tion into this organ of an acid of 
some kind. This is done most 
easily by injecting the acid, either 
in solution in water or in a " phys- 
iological " salt solution, directly 
into the general circulation of an 
animal. For this purpose I used, 
in my own experiments, a large- 
sized aspirating syringe with a 
two-way valve, rubber tubing and 
a hypodermic needle, as illustrated 
in Fig. 143. The acid solution 
warmed to 37° C. is sucked into 
the syringe through the tube a. 
After turning the valve v it can be 
ejected, on lowering the plunger, 
through the tube b, which ends in 
the hypodermic needle n. The 
needle is inserted into the ear vein 
of a rabbit and is held in place by 
a couple of small artery forceps. As 
the acid is injected intravenously, 
one observes the normally alkaline 
urine of the rabbit to become neutral 
and then to turn acid, and as this 
acidity rises, albumin appears in 
the urine. The following experi- 
ments dealing with the effects of 
such intravenous acid injections will 
serve to illustrate this point. Let 
it be noted that in addition to the 
appearance of albumin in the urine, this comes to contain various 
casts, epithelial cells, blood corpuscles and hemoglobin. By 




I* 



Figure 143. 



490 



(EDEMA AND NEPHRITIS 



comparing the urinary output in these animals with that shown 
by normal animals, 1 it is seen that this is decreased. Evi- 
dences of cedema are also not wanting; animals injected with an 
acid do not excrete the water that is injected with this acid as 
does a normal animal that is given water only, in the form of a 
" physiological " salt solution. The water when injected with an 
acid is retained in the body, but to this phase of the problem of 
nephritis we shall need to return later. For the present it is clear 
that there develop all the most typical signs of an acute nephritis 
when acid in sufficient amount is injected into an animal. 

Experiment 59. — Belgian hare; weight 1870 grams. Has been 
fed corn, oats, hay, and cabbage. Urine obtained by gentle manual 
pressure over the bladder. 2 In the time of the experiment there are 
injected, at 37° C. and at a uniform rate, with the exceptions noted, 
291 cc. of the following mixture: 300 cc. n/20 HC1+20 cc. 2/in 
NaCl. 



Time. 


Amount of 


Remarks. 


urine in cc. 


1.20 




Tied to animal board. No anesthetic. 


1.45 
2.00 


- " .0\ 
6.0i 


Turbid, yellow, no albumin, no casts. 




Injection into ear vein begun. 


2.15 


Few drops 


Turbid, yellow, no albumin, no casts. 


2.30 


1.9 


Clear, yellow, faint trace albumin, no casts. 


2.45 






3.00 


1.5 


Clear, brownish tinge, albumin present, few red blood cor- 
puscles, isolated kidney cells, no casts. 


3.15 
3.30 


1.6} 
1.3/ 


Smoky urine, albumin, isolated granular and epithelial casts. 


3.45 


2.2 


Smoky urine, albumin, isolated granular and epithelial casts. 
Injection interrupted for 2% minutes. 


4.00 


4.8 


Smoky urine, albumin, isolated granular and epithelial casts. 
Injection interrupted for five minutes. 


4.15 


1 ( 


Smoky urine, albumin, isolated granular and epithelial casts. 


4.45 


} 21.0 I 


Hemoglobinuria. Injection interrupted for ten minutes. 


5.00 


J 


Animal dies. 





1 See pages 334 and 340. 

2 In these experiments on nephritis the greatest care is necessary not to 
injure the lower urinary passages and so get a bleeding which might, through 
the presence of albumin and blood in the urine, lead to the erroneous con- 
clusion that a nephritis is at hand when only some bleeding is occurring 
into the bladder or urethra. Manual pressure over the bladder must be 
made with gentleness, and care must be taken not so to crowd the bladder 
into the pelvis as to kink the urethra. Only the smallest soft rubber catheter, 
well vaselined, must be introduced. If these precautions are not followed, 
fallacious, if not worthless, results are obtained. When an animal dies or ifi 
killed, the lower urinary passages must be examined for hemorrhagic points* 



NEPHRITIS 



491 



Total urine secreted since beginning injection 34.3 cc. 

Autopsy. — Weight of animal 2135 grams! No free fluid in peri- 
toneal, pericardial, or pleural cavities. Kidneys slightly bluish, and 
bleed freely on section. Nothing about them is strikingly abnormal. 

Experiment 60. — Belgian hare; weight 2008 grams. Has been 
fed a mixed diet of corn, oats, hay, and cabbage. Urine obtained by 
gentle pressure over bladder. During the course of the experiment 
there are injected at 37° C, and at a uniform rate with the excep- 
tion noted, 90 cc. of the following mixture: 90 cc. n/10 HC1 +6 cc. 
2/m NaCl. 



Time. 


Amount of 
urine in cc. 


Remarks. 


3.35 




Tied down. No anesthetic. 


3.40 




Injection into ear vein begun. 


3.55 


6.0 


Turbid, yellow, alkaline to litmus. No albumin, no casts. 


4.05 


1.7 


Clearer, trace of albumin present. 


4.20 


0.8 


Urine smoky, albumin increasing. Injection stopped for fifteen 
minutes as animal threatens to die. 


4.40 




Injection recommenced. 


4.45 


Few drops 


Bloody, much albumin, red blood corpuscles, great numbers of 
granular casts of various sizes. 


4.47 




Animal dies. 



Total urine secreted since commencing injection 8.5 cc. 

Autopsy. — Weight 2078.5. No free fluid in the peritoneal, pleural, 
or pericardial cavities. Kidneys slightly swelled. Under the cap- 
sule appear tiny hemorrhagic points. 

Experiment 61. — Belgian hare; weight 2259 'grams. Diet unknown, 
as he has just been received in the laboratory. Urine obtained with a 
catheter. In the course of the experiment 75 cc. of the following solu- 
tion are injected intravenously at a uniform rate, with the exception 
noted: 75cc.n/10HCl +5 cc. 2/m NaCl. 



Time. 


Amount of 
urine in cc. 


Remarks. 


11.30 


7 





Tied to animal board. Urine thick, chrome yellow, no albumin. 


11.45 


19 


4 


Thick, chrome yellow, no albumin, alkaline to litmus paper. 


12.00 
12.15 






Injection into vein of ear begun. 


2 





Thick, chrome yellow, no albumin, alkaline to litmus. 


12.30 


1 


6 


Clearer, pinkish tinge, albumin present. 


12.40 






Injection stopped entirely. 


12.45 


3 


7 


Urine distinctly red, much albumin, many casts. 


1.45 


11 


5 


Urine turbid, red, shows spectrum of oxyhemoglobin, filled with 








albumin, casts, (epithelial, granular and mixed), epithelial 








cells and red blood corpuscles. Animal released in good 








condition, returned to hutch. 



492 (EDEMA AND NEPHRITIS 

Total urine secreted since beginning injection 19.2 cc. 



5.30 5.0 r 

per cathe-j Clear, yellow, acid. Casts and albumin still present, 

ter. I » 

11.00 (" 37.0 f Dark amber, thick, faintly acid, clear. Microscopic examina- 

Next <j per cathe-i tion shows many squamous epithelial cells and isolated casts, 

morning [ ter. [ Carefully filtered urine shows a trace of albumin. 



These nephritides produced experimentally in animals have a 
perfect parallel in the albuminurias with blood, casts, and a 
diminished urinary output to the point of cessation which are 
observed from time to time in human beings who have 
inhaled or swallowed by accident or intent sufficient quantities 
of various acids. 

§2 

It will be retorted by some that to inject acid intravenously 
is so " abnormal " that it and its consequent nephritis has noth- 
ing in common with the albuminurias and nephritides observed 
in human beings. To meet this criticism it is only necessary 
to examine the urine in conditions in which large amounts of 
acid are produced " physiologically " within the body itself. 
As is well known, large amounts of acid (especially lactic acid) 
are produced in the muscles when these contract. If the muscle 
works under physiological conditions and not too fast, the acid 
as formed may be largely oxidized in situ. But if the muscle 
works more rapidly then more acid is produced than can be 
oxidized in the muscles and so in the higher animals some passes 
unchanged into the blood, with this to the kidneys, and out in 
the urine. 1 It is evident that the opportunities for such an 
accumulation of acid in the body become the greater the more 
rapidly and the harder the musculature of the body works, 
and we should add, the more defective the oxygen supply to 
the working muscles, for this element is necessary for the proper 
oxidation of the acid in the body. Now such a combination 
of hard work with a (temporarily) defective oxygen supply to 
the active muscles is furnished whenever the organism engages 
in exercise that calls for more than usual effort. We are therefore 

1 Trasaburo Araki: Zeitschr. f. physiol. Chemie, 19, 422 (1894), where 
references to his earlier papers may be found. Hoppe-Seyler : ibid., 19, 
476 (1894). Fletcher and Hopkins: Jour. Physiol., 35, 247 (1907). 



NEPHRITIS 



493 



not surprised to find that soldiers after prolonged marches, 
women in labor, Marathon runners, etc., show albumin, casts, 
blood, etc., in the urine when examined after such exertions. 1 
The amount of exercise needed to bring about such albuminurias 
is really surprisingly low, as is indicated by the following: 

Experiment 62. — Seven trained athletes just before entering 
upon a game of basket ball were asked to void their urine into a series 
of flasks. At the end of the game, which lasted l\ hours, they voided 
their urine a second time into a second series of flasks. Heller's 




Figure 144. Figure 145. 



test was then applied to the various specimens of urine. While none of 
the players showed any trace of albumin in his urine before the play, all 
gave marked reactions after the game. The results of the tests applied 
to the urines voided after the game are shown in Figs. 144 and 145. 
The first four tubes are photographed against a white background, 
the three of Fig. 145 against a black. The faint albumin ring present 
in the tube on the extreme right of Fig. 145 scarcely shows in the photo- 
graph. Interestingly enough, this specimen of urine came from a player 
who was in the game but five minutes. 

Experiment 63. — Five trained athletes shortly before engaging 
in a match game of basket ball void their urine into a series of flasks. 

1 W. Leube: Virchow's Arch, 72, 145 (1878). G. Edlefsen: Centralbt. 
f. d. med. Wissensch., 762 (1879). C. von Noorden: Arch. f. klin. Med., 
38, 205 (1886). 



494 



(EDEMA AND NEPHRITIS 



All the urine voided during the succeeding l\ hours during which the 
game is played is collected in a parallel series of flasks. In none of 
the control urines with the exception of that of Player IV are there 
found albumin or casts. This player had found it necessary before 
coming to the game to rush about town making train and street-car 
connections and had moreover had a " cold " for three days previ- 
ously. After the game all the players showed an albuminuria and a 
great many granular, hyaline, and mixed casts. The albumin and the 
casts in the previously affected individual were markedly increased. 
The findings are illustrated in Fig. 146 and in the appended Table 




Figure 146. 



CIV. The five tubes on the right show the results of applying the 
cold nitric acid test to the urine after the game. The tube on the 
extreme left shows the albuminuria existing in Player IV even before 
entering the game. The quantitative estimations in the Esbach 
tubes were carried out in the ordinary way using Tsuchiya's 1 phos- 
photungstic acid reagent. The photograph was made after the tubes 
had stood for only six hours. The readings in the table were made 
after twenty-four hours. 

1 Tsuchiya: Centralbl. f. inn. Med., 29, 105 (1908). 
Phosphotungstic acid, 1.5 grams. 
Concentrated hydrochloric acid, 5 cc. 
Alcohol enough to make 100 cc. 



NEPHRITIS 



495 



TABLE CIV 

Before the Game 



Player 


Amount of 
urine in cc. 


Nitric acid test. 


Casts. 


I 


60 


Negative 


None 


II 


158 


Negative 


None 


III 


5 


Negative 


None 


IV 


47 


Positive 


Occasional granular 








and hyaline 


V 


134 


Negative 


None 



After the Game (1} Hour Period). 



Player. 


Amount of 
urine in cc. 


Nitric acid 
test. 


Casts. 


Esbach reading 
with phospho- 
tungstic acid. 


Albumin 
excreted in 
grams. 


I 
II 
III 

IV 
V 


168 
69 

35 
30 
94 


Positive 
in all 


Many hyaline, 
granular and 
mixed casts 
present in all. 


0.6 

3.25 

2.3 

5.0 

2.75 


0.111 
0.224 
0.080 
0. 150 
- 0.258 












A v . 163 



A remarkably short period 
produce a great albuminuria, 
as the following taken from 
many such observations 
shows: 

Experiment 64. — B , a 

well-trained and expert Univer- 
sity runner ran a quarter-mile 
race. Before starting he voided 
54 cc. of urine which on exami- 
nation showed no albumin. After 
his race (time: 58 seconds!) he 
voided 59 cc. of urine in which 
much albumin was found. In 
Fig. 147 are shown the results of 
the albumin tests as applied to 
the two samples of urine. In the 
two tubes on the right the cold 
nitric acid test has been applied 
to the urines; in the tube on 
the left a quantitative estimation 
has been carried out in an Esbach 
tube with Tsuchiya's phospho- 
tungstic acid reagent. 



of hard athletic work suffices to 



J 

i 


1 

i 


1 1 


I 








• 


• 




A 



Figure 147. 



496 



(EDEMA AND NEPHRITIS 



§ 3 

A condition in the body analogous to that produced vol- 
untarily by the athlete in his athletic activities is created 
through any uncompensated heart lesion or any disease of the 
lung of such a character as to interfere materially with the 
proper aeration of the blood. Under these circumstances there 
is not produced the excessive amount of acid by extra mus- 
cular exertion, but the oxidation of such amounts as are 
normally present has been decreased by not permitting the nor- 
mal amount of oxygen to get to the tissues of the body. The 
end result is, of course, the same. A defectively functioning 
heart or a sufficiently disabled lung interferes first of all with 
the proper escape of carbonic acid from the blood (and so from 
the cells in which this is produced). 1 But they do more than 
this, they place the organism as a whole in a state of lack of 
oxygen, and as a necessary consequence of this we know from 
the studies of Trasaburo Araki, 2 Hermann Zillessen, 3 and 
P. von Terray 4 that we get an abnormal production and 
accumulation of other acids, notably lactic and oxalic acids, 
in the tissues. Heart or lung lesions therefore are potent to 
lead to that same abnormally high acid content of the cells of 
the kidney that we previously found created through the direct 
injection of acids, or the hard work of the athlete, and so we are 
prepared to find in these pathological states of the heart and lung 
that albuminuria with casts, and a defective secretion of water 
is again a common consequence. As a matter of fact the associa- 
tion of " nephritis " or "Bright's disease " with heart lesions of 
the most varied kinds, or pathological conditions in the lung 
(manual compression of the thorax, pleurisy with effusion) that 
reduce its ventilation area sufficiently, is so constantly observed 
that it is taken for granted clinically. 

1 Stkassburg: Pfluger's Arch., 6, 94 (1873); A. Ewald: Arch. f. (Anat. 
und) Physiol., 663 (1873); 123 (1876). 

2 T. Araki: Zeitschr. f. physiol. Chemie, 15, 335 and 546 (1891); 16, 
453 (1892); 17, 311 (1893); 19, 422 (1894). 

3 H. Zillessen: Zeitschr. f. physiol. Chemie, 15, 387 (1891). 

4 P. von Terray; Pfluger's Arch., 65, 393 (1896). 



NEPHRITIS 



497 



§ 4 

It requires no special comment to recognize that a whole 
series of pathological states such as the severer anemias, carbon 
monoxid poisoning/ and epileptic seizures, which at first sight 
seem to have nothing in common with each other, contain within 
themselves all the elements necessary for the development of 
the signs of a nephritis. The severe anemias (leukemia or per- 
nicious anemia) merely constitute further ways of interfering 
with a proper oxygen supply to the tissues. Both are accom- 
panied by an abnormal storage and production of acid in the 
tissues as evidenced by Felix Hoppe-Seyler's 2 and T. 
Irasawa's 3 chemical analyses of the urine, and R. von Jaksch's 4 
titrations of the blood in cases of severe anemia. An abnormal 
acid production in carbon monoxid poisoning has been proved 
by T. Araki, 5 E. Munzer and P. Palma; 6 in epilepsy (severe 
muscular exertion with defective breathing) by Araki and 
E. Mendel. As clinicians well know, the finding of albumin, 
casts, blood, etc , in the urine in any of these pathological states 
is usual. 

§5 

The etiological importance of " cold " (in the strict sense 
of the word as a lowering of the body temperature and unac- 
companied by an infection) in the production of an acute nephritis, 
or in the lighting up of a chronic one that has slumbered for 
a time, has always been insisted upon by earlier observers. 
This view finds a rigid scientific support in our present knowledge 
of the physiological effects of low temperature upon the warm- 
blooded animals. Of these none is more characteristic than the 
rise in the acid content of the cells of an animal so exposed. 7 

1 G. Thompson: Trans. Assoc. Am. Physicians (1902); William Ravine: 
Personal communication. 

2 F. Hoppe-Seyler: Zeitschr. f. physiol. Chemie, 19, 473 (1894). 
3 T. Irasawa: Zeitschr. f. physiol. Chemie, 15, 380 (1891). 

4 R. von Jaksch: Klinische Diagnostik, 5th Ed., 2, Berlin (1901). 

5 T. Araki: Zeitschr. f. physiol. Chemie, 15, 335 (1891). 

6 E. Munzer and P. Palma: Prager Zeitschr. f. Heilk., 15 (1894). 

7 See Araki: Zeitschr. f. physiol. Chemie, 16, 453 (1892). On the basis 
of this same acid production we can with ease explain the precipitation of 
an attack of hemoglobinuria in the cases of so-called paroxysmal hemo- 



498 



(EDEMA AND NEPHRITIS 



How potent is this element of cold in leading to the signs of 
a nephritis has been well brought out by R. D. Kennedy, 1 who 
in Northern Michigan (Calumet) during extremely cold weather 
found albumin in 40 per cent of all patients examined who had 
been exposed to it. Thirteen of fourteen physicians in the 
hospital had albumin and casts in their urines some time through 
the winter. The only exception was an eye specialist who 
worked indoors. But even more trivial exposures to cold suffice 
to bring about these consequences. A cold bath, for example, 
leads, in not a few individuals, to the appearance of albumin 
in the urine. 

§6 

Thus far we have discussed only general conditions — con- 
ditions affecting the whole animal — that are capable of indu- 
cing an abnormal storage or production of acid in the body, and 
so of inducing a nephritis. We shall now consider a series of 
more local conditions that bring about the same result. 

Instead of interfering with the normal action of the heart 
or lungs an effective state of lack of oxygen in the kidney can, of 
course, be induced by direct interference with the normal blood flow 
through this organ. Experimentally such a condition is easily 
established by total or partial ligation of either the arterial or the 
venous blood supply of this organ, a state that has its clinical par- 
allel in such affections as partial or complete occlusion of the renal 
vessels through arteriosclerosis, thrombosis, embolism or the pres- 

globinuria when these patients take a cold bath, are exposed to cold, etc. 
The acid produced under these circumstances rises to the point where it 
leads to hemolysis of the patient's red blood corpuscles. This view is sup- 
ported by the fact that it is possible to precipitate an attack of hemoglo- 
binuria for diagnostic purposes quite as easily through temporary obstruc- 
tion of the circulation in the arm by applying a band about it (accumulation 
of carbonic acid and production of other acids due to a lack of oxygen) 
as through the customary immersion of the extremities in cold water. The 
essential nature of the paroxysmal hemoglobinurias would seem to reside 
in the lesser resistance which the red blood corpuscles of such patients 
have to such a hemolytic agent as an acid. The resistance is enormously 
increased by the addition of various salts to the blood, as Oscar Berghausen 
has shown. This fact is not only of theoretical interest, as I have tried to 
show in discussing the nature of hemolysis (see page 438 or Fischer: Kolloid- 
Zeitschr., 5, 146 (1909)) but of practical use in the treatment of these cases of 
hemoglobinuria which need a diet rich in alkalies, calcium salts, etc. 
1 R. D. Kennedy: Personal communication (1912). 



NEPHRITIS 



499 



sure of tumors, etc., upon these vessels. But as the experiments of 
T. Araki and H. Zillessen have shown, such an interference with 
the normal blood supply (oxygen supply) to any of the parenchym- 
atous organs is followed immediately by the accumulation of 
acids in the affected tissues. Do we find that in such local cir- 
culatory disturbances of the kidney we get an albuminuria? 
That we do is, of course, known to everyone — it constitutes, 
since Max Herrmann's 1 experimental studies, one of the classi- 
cal facts of pathological physiology; it is attested to by the 
experience of the medical diagnostician; it is the bugbear of sur- 
geons who operate on the kidney and find a temporary closure 
of the renal vessels expedient or necessary, 2 

§7 

Instead of interfering directly with the oxygen supply to the 
kidney by procedures which interfere with the blood supply to 
this organ, we can bring about the same result in a more subtle 
way by giving the kidney parenchyma its normal oxygen supply, 
but by so interfering with the chemistry (enzymotic processes) 
of the cells themselves that make up the kidney as to render 
these incapable of utilizing in proper form the oxygen that is 
freely supplied them. So far as the end result is concerned, it 
matters little, of course, whether we interfere with the normal 
oxidation, say, of the carbohydrates of the living cell to carbonic 
acid by shutting off the oxygen supply to the cell and so halting 
the decomposition of the carbohydrates when these have been 
changed to lactic, oxalic, formic and other acids (saccharinic 
acids) ; 3 or whether we do nothing about the oxygen supply but 

1 Max Herrmann: Sitzungsber. d. Wiener Acad., math -phys., Klasse, 
65 (1861). 

2 For a discussion of the methods to be employed in combating the evil 
consequences of such temporary closure see the section dealing with the 
treatment of nephritis. 

3 The chemical aspects of this problem of the formation of acids from 
carbohydrates in the absence of oxygen are discussed by Felix Hoppe-Seyler : 
Berichte d. deut. chem. Gesellsch., 4, 346 (1871); H. Kiliani: ibid., 15, 701 
(1882); Duclaux: Compt. rend., 94, 169; Schutzenberger: ibid., 76, 
470; Buchner, Meisenheimer, and Schade: Berichte d. deut. chem. 
Gesellsch., 39, 4217 (1906); J. U. Nef: Liebig's Annalen, 357, 214 (1907). 
The biochemical aspects of this same problem are discussed in the papers 
on lack of oxygen already referred to on pages 235 and 273. 



500 



(EDEMA AND NEPHRITIS 



introduce something into the cell which prevents the oxidation 
of the lactic acid as formed (or more probably its mother sub- 
stance, glycerin aldehyd) to carbonic acid. 1 The cells of the 
living body in the end get into the same state whether they have 
their oxygen supply cut off or whether this is not interfered with, 
but they are " poisoned " in such a way as to be unable to utilize 
this oxygen as normally. 

As has been shown particularly well by T. Araki, a large 
number of poisons lead to the same state of lack of oxygen, with 
its associated abnormal production and accumulation of acids 
in the tissues, as do the grosser interferences with the oxygen 
supply to the various organs or the body as a whole, that have 
already been described. And so it cannot surprise us to discover 
that Araki's list of poisons — poisons utilized to show that an abnor- 
mal acid production is the constant accompaniment of a state of lack 
of oxygen in the tissues no matter how produced — is identical with 
the list of poisons familiar to any laboratory or clinical worker who 
has busied himself with the problem of the toxic nephritides: metallic 
salts, such as those of arsenic, uranium, chromium and lead; 
alkaloids, such as morphin, cocain, veratrin and strychnin; anes- 
thetics, such as alcohol, acetone, ether and chloroform; unclas- 
sified poisons, such as amyl nitrite, the cyanids and phosphorus. 

§ 8 

In concluding this section we need to discuss the albuminurias 
encountered in three conditions which not only are readily inter- 
pretable on the basis of our contention that albuminuria results 
whenever abnormally great amounts of acid accumulate in the 
kidney, but give this contention valuable support. 

Since Rudolph Virchow's description of the condition fifty 
years ago, the albuminuria of the newborn constitutes a matter of 
common knowledge to every pediatrist. It occurs in perfectly 
healthy infants as a transitory phenomenon, is regarded as " phys- 
iological," and to it ordinarily no clinical importance is attached. 
Whence comes it? The condition is most commonly found in 
" hard " labors, when the cord prolapses, in breech presentations, 
etc., all of them conditions which mean a state of more than the 

1 In this connection see the interesting work of R. T. Woodyatt: Jour. 
Am. Med. Assoc. 55, 2109 (1910). 



NEPHRITIS 



501 



normal lack of -oxygen in the organism of the child during the 
process of its birth. Even normal labor means, of course, a decided 
interference with the circulation of the infant — is it not in this 
fact and the associated accumulation of carbonic acid and other 
acids in the blood that the cause of the first respiration is to be 
sought, as Zuntz has shown? Difficult labors mean in toto 
only a more than usual interference with the circulation of the 
child. It is entirely a matter of definition as to just how much 
of this we will accept as " physiological." But when we have 
thus connected the development of the albuminuria with a dis- 
turbance in the general circulation of the child then we have 
made it, at the same time, a mere subheading of the albuminurias 
discussed in § 3 of this section (page 496), and the albuminuria 
is " physiological " only as we will accept little or great inter- 
ference with the circulation in the infant during its birth as 
" physiological." , 

Albuminuria is a common accompaniment of salt starvation, 
be this a complete salt starvation or only such a partial one as 
is induced by eliminating completely the sodium chlorid from 
the food. Under this same heading is to be classed the albu- 
minuria consequent upon the excessive consumption of water low 
in salts. The latter washes the salts out of the body 1 and so 
leads indirectly to the same state as that induced by a lack of 
salts in the diet. The effect of a salt-free diet is twofold. In 
the first place it leads to the accumulation of acids in the tissues. 2 
Other things being equal, we have on this basis alone therefore 
a reason for the appearance of the urinary findings characteristic 
of nephritis when salts are withheld from the diet. But the salts 
act in yet another way. As already discussed, and as we shall 
see in greater detail later, many of the changes induced in colloids 
by acid may be greatly inhibited through the presence of all salts, 
even neutral salts incapable of an effect that might be construed 
as due to a mere neutralization of the acid. Through the with- 
drawal of salts from the tissues, whether by salt starvation or 
through leaching these out with water, we favor, therefore, the 
development of the signs of a nephritis in two ways: not only do 
we render possible an abnormal production or accumulation of 

1 See page 368. 

2 G. Bunge: Zeitschr. f. Biol., 10, 111 (1874); see also J. Forster: ibid., 
9, 297, 369 (1873); N. Lunin: Zeitschr. f. physiol. Chemie, 5, 31 (1881). 



502 



OEDEMA AND NEPHRITIS 



acids in the tissues, but we take away at the same time the action 
of the salts in reducing the effect of the acids. 

IV 

NEPHRITIS DUE TO OTHER THAN ACID CAUSES 

The colloid changes in the kidney which are characteristic 
of nephritis and which we shall discuss in greater detail later, 
such, for example, as the swelling of the kidney, are inducible, 
as previously noted, by other substances besides acids. Any 
agency thus capable of increasing the hydration capacity of 
a protein colloid and under physiological or pathological cir- 
cumstances conceivably active in a kidney may in this way 
become a cause of the nephritic signs. Of the various ones 
which might be mentioned (alkalies, urea, pyridin, certain amins) 
and touched upon in the discussion of oedema, we shall here 
consider only the first, namely, the alkalies, in illustration of 
this point. 

It so happens that the sum total of the chemical changes that 
go on in the living animal organism are of such a character as to 
threaten it chiefly from the acid side. Even under normal con- 
ditions, the tissues have to guard themselves against becoming 
acid. Is not carbonic acid among the chief end products of the oxi- 
dation of our foodstuffs? The normal tendency of the tissues to run 
over to the acid side is enormously increased under various patho- 
logical conditions, and as we shall find these conditions to be just 
such as are likely to lead to a nephritis, the discussion of this sub- 
ject will naturally claim our chief attention. An abnormally high 
alkali content in the cells under ordinary circumstances is scarcely 
possible, and when it is induced artificially it is difficult to main- 
tain, for the normal acid production (carbonic acid production) 
in the living cell tends quickly to neutralize it. This question is, 
therefore, scarcely to be considered in our further analysis of 
the problem of nephritis. Still, from a theoretical standpoint 
and in poison cases it is quite as important as that upon which 
we shall lay the greater stress. We should, on the basis of our 
colloid conceptions of nephritis, be able to induce this condition 
experimentally quite as easily through alkalies as through acids. 
As the following experiments show, this is actually the case. 



NEPHRITIS 



503 



Experiment 65. — Belgian hare; weight 2085 grams. Has been 
fed hay, oats, corn and cabbage. In the course of the experiment 
there are injected intravenously at a uniform rate 125 cc. of the fol- 
lowing mixture: 150 cc. n/10 NaOH+10 cc. 2/m NaCl. 



Time. 


Amount of 
urine in cc. 


Remarks. 


2 


35 


31.0 


Catheterized. Dark amber, acid to litmus paper. No albu- 








min. No casts. 


3 


15 


0.7 


Weighed. Placed in animal board. Injection into ear begun. 








No albumin. No casts. Acid in reaction. 


3 


30 


1.2 


Urine clearer. Acid in reaction (?) Trace of albumin (?). 


3 


45 


8.4 


Milky, alkaline to litmus. Faint trace of albumin. 


4 


00 


6.0 


Milky, alkaline to litmus. Isolated casts. Faint trace of 








albumin. 


4 


15 


1.2 


Milky, alkaline to litmus. More albumin. Many long hya- 








line casts with coarsely granular material sticking to them. 


4 


30 


0.7 


Milky, alkaline to litmus. Much albumin. Filled with casts. 


4 


45 


0.4 


Filled with casts. Bloody tinge to urine. 


4 


58 


0.4 + 


Milky, alkaline to litmus. Much albumin. Filled with casts. 








Bloody tinge to urine. Animal dies. 






0.6 con- r 


1 . gram of feces lost. It is noted that the albumin reactions 






tained J 


as obtained with cold nitric acid applied to the filtered acidi- 






in cathe- | 


fied urine are not as intense as in the albuminurias induced 






ter. 1 


by acid injections. (Less albumin?). 



Total urine since beginning injection 18.9 cc. 

Autopsy. — Weight 2187 grams! No fluid in the cavities. Intes- 
tinal "contents seem somewhat more fluid than usual. Kidneys are 
firm, apparently somewhat swelled, and do not bleed easily. 

Experiment 66. — White rabbit; weight 1911 grams. Fed hay, 
oats, corn, and greens. In the course of the experiment there are 
injected at a uniform rate 185 cc. of the following mixture: 225 cc. 
n/10 NaOH+15 cc. 2/m NaCl. 



Time. 



Amount of 
urine in cc. 



Remarks. 




Catheterized. Turbid, dark amber, acid. No albumin, no casts. 
Turbid, dark amber, acid. No albumin, no casts. 
Weighed. Injection into ear vein begun. Urine as before. 
Urine as before. 

Neutral to litmus. Clearer. Small amount of albumin. 

Many hyaline casts. Some have coarse granules in them. 
Urine clear as water. Some albumin. Many hyaline casts. 

Some have coarse granules in them. 
Urine clear as water. Only a few casts can be found. Albumin 

present. 

Weakly alkaline. Albumin present. Isolated casts only can 
be found. 

Albumin present. No casts can be found. The urine has a 
pink tinge (hemoglobinuria). No red blood corpuscles 
microscopically . 

Injection stopped. 

Faintly alkaline. Clear, pink, no casts, no red blood corpus- 
ties. Albumin present. Animal released. Seems entirely 
normal, and eats at once. 



Total urine since beginning injection, 92.6 cc. 
Weight 2000 grams! 



504 



(EDEMA AND NEPHRITIS 



Experiment 67. — White rabbit: weight 2177 grams. Fed hay, 
oats, corn, and cabbage. In the course of the experiment there are 
injected at a uniform rate 240 cc. of the following mixture: 225 cc. 
n/20 NaOH+15 cc. 2/m NaCl. Injection made into ear vein. 



Time. 


Amount of 


Remarks. 






urine in cc. 


1 


50 


10.0 


Catheterized. Turbid, yellow urine. No albumin. No casts. 


2 


00 




Weighed. 


2 


15 


1 drop 


No albumin. Injection begun. 


2 


30 






2 


45 


0.2 


Albumin present. Filled with casts, mainly hyaline in char- 
acter, but some are finely granular. Much squamous epi- 
lium and cell detritus. 


3 


00 


0.5 


Alkaline to litmus. Albumin and casts as before, but all the 
casts are hyaline except for coarse, granular material con- 
tained in or attached to some. 


3 


15 


0.2 


Strongly alkaline. Albumin and casts as before. 


3 


30 


2 drops 


Strongly alkaline. Albumin and casts as before. The urine 
has a pinkish tinge (hemoglobinuria). 


3 


45 


1.0 


Strongly alkaline. Albumin and casts as before. Urine pink- 
ish (hemoglobinuria). Red blood corpuscles are found and 
two microscopic blood coagula. This bleeding is attributed 
to traumatism (animal struggled and whipped catheter 
about) . 


4 


00 


2.8 


Urine strongly alkaline. The animal has begun to shiver (acid 
production!) during the last fifteen minutes. The previously 
warm ears are pale and cold. 


4 


15 


13.0 T 


The urine becomes faintly alkaline, then scarcely affects either 


4 


30 


12.0 


red or blue litmus. The urine is clear like water except for 


4 


45 


16.0 \ 


a clouding due to (traumatic) blood. Careful search of the 


5 


00 


19.0 


sedimented urine reveals only an occasional cast. The 


5 


15 


23.0 J 


animal is shivering constantly. It is killed. 



Total urine since beginning injection, 87.7 cc. 

Autopsy. — Weight 2326 grams! The peritoneal, pleural, and 
pericardial cavities are dry. The kidneys are soft and bleed a normaL 
amount. A few pinpoint hemorrhagic spots are found in the bladder. 



V 

THE ALBUMINURIA 
1. Introductory Remarks 

Having discussed the evidence which shows that an abnormal- 
production or accumulation of acid (alkali, pyridin, urea, amins) 
occurs in the kidney in every case of nephritis, and, conversely, 
that whenever such is brought about, the signs of nephritis 
become manifest, we need now to say how such a single factor 
is able to produce the various objective signs which as clinicians 
we have come to regard as characteristic of this pathologicaL 
entity. The first to be considered is the albuminuria. 



NEPHRITIS 



505 



The urine of man or of the various animals that serve us 
for experimental purposes does not under normal circumstances 
contain albumin in an amount that betrays itself when any of 
our ordinary laboratory tests are applied to it. By special 
methods it is possible to show that even such normal urine con- 
tains faint traces of albumin, but it is generally held that this is 
of no pathological significance and has behind it a no more serious 
cause (it is thought) than the shedding and destruction of a few 
cells from the tract through which the urine has to pass from the 
uriniferous tubules into the outer world. An albuminuria, as 
we shall use the term, will, therefore, have a meaning only as 
applied to the presence of albumin beyond this normal amount, 
and, we ought to add, of renal origin and not from somewhere 
below this organ. Nor has the mechanism of the albuminuria 
which we are discussing anything in common with the albu- 
minuria consequent upon gross destructive lesions in the kidney 
as when small or large blood vessels are ruptured, allowing 
their entire contents to escape into the urine. 

Our current hypotheses regarding the cause of albuminuria 
are familiar to everyone and are notoriously unsatisfactory. It 
is generally held that the (chief) albumin of albuminuria is serum 
albumin, that it is derived from the blood, and that it is under 
normal circumstances prevented from going over into the urine 
by the kidney structures which lie between the urine and the 
blood. Some twenty years ago R. Heidenhain attempted to 
express the whole situation in satisfactory physico-chemical 
terms. He pointed out the colloid nature of the blood albumins, 
and called to mind Thomas Graham's fundamental differentia- 
tion between the colloids which do not diffuse through animal 
membranes and the crystalloids which do this readily. On this 
basis he maintained that the latter appeared in the urine because 
they could readily diffuse through the animal membrane that 
separates the urine from the blood, while albumin is absent 
because this colloid body cannot diffuse through such a mem- 
brane. We have not since Heidenhain' s considerations gotten 
beyond this view. 

Simple and apparently satisfactory as this explanation is, 
it cannot stand the pressure of a little analysis. In nephritis 
this membrane is, of course, still present, and yet in this patho- 
logical state the albumin appears in the urine. To meet this 



/ 



506 



(EDEMA AND NEPHRITIS 



fact it has been generally maintained, and, let us add, without 
any experimental support whatsoever, that the " permeability " 
of the urinary membrane for albumin has been altered, so that 
it now lets this through. As a matter of fact, we have not even 
had offered us any parallel from the pages of physical chemistry 
for such a change in the permeability of any " membrane " that 
in the laboratory corresponds with such as we might have in 
the body, nor, so far as I know, has anyone attempted to say just 
what chemical or physico-chemical agent is responsible for the 
changes in permeability postulated in the case of the kidney. 

A first error in this theory of albuminuria (which represents 
the epitome of our present conceptions regarding its nature) 
arises from the fact that the albumin found in the urine is looked 
upon as coming from the blood. Such a belief has been entertained 
because it has been found that the albumin present in the urine 
shows a series of reactions which are identical with those obtained 
from serum albumin. But this does not yet prove that the 
albumin of albuminuria has come directly from the blood. Such 
a conclusion overlooks the important fact that the albumins 
contained in the kidney itself, in other words the albumins 
contained in the secreting membrane separating the urine from 
the blood, also show these reactions. None of the albumin 
reactions used in these tests is " specific." They only represent 
certain group reactions which colloid chemistry has shown us 
to be common to a large number of the protein colloids of animal 
origin. Such considerations carry with them the important 
conclusion that the albumin of albuminuria need not come from 
the blood at all (except indirectly); it may come from the urinary 
membrane itself. That, as a matter of fact, it does come from 
this will appear more distinctly as we proceed. Albuminuria 
results whenever conditions are offered in the body which permit 
the solid colloid membrane that separates the blood from the urine 
to go into solution in the urine. The chief reason why this occurs 
in nephritis resides in the fact that acids are produced which 
render the colloid membrane " soluble." To make clear what is 
meant by this conclusion we need but recall our previous remarks 
on the general structure of the kidney 1 and introduce some 
observations on this question of the " solubility " of colloids. 

Many scattered but important facts regarding this problem 
1 See page 326. 



NEPHRITIS 



507 



are found in the literature of colloid chemistry, especially if we 
bear in mind that the " solution " of a protein is, in all prob- 
ability, not a simple affair. We have learned how under the 
influence of an acid, the protein particles are hydrated and in 
increasing amount with increasing concentration. But under the 
same influence, as the " dissolved " state is approached, new 
properties are likely to be exhibited by the protein as indicated not 
only by a fall in its viscosity but by changes in its diffusibility, 
Brownian movement, susceptibility to precipitation, etc. The 
protein moves from a state in which it is markedly colloid toward 
the crystalloid side. Technically put, its degree of dispersion is 
increased. 

An increase in swelling followed later by a decrease, an 
increase in viscosity giving way to a decrease, an increase in 
diffusibility, or in Brownian movement may all therefore be 
regarded as evidences for an increased " solubility." If this 
is borne in mind then Thomas Graham becomes one of the first 
students in this field, for he noted that the addition of acetic 
acid to egg albumin increased its diffusibility. On the other 
hand, E. von Regeczy 1 found the addition of sodium chlorid 
to delay its diffusion. 

Particularly important for our purposes are the studies of 
T. B. Wood and W. B. Hardy, 2 who found plant protein (glu- 
ten) to maintain its " cohesiveness " (remain solid) in water 
and neutral media but to " disintegrate " and " dissolve " 
when a little acid was added. The solution in acid depended 
upon the nature and the concentration of the acid and was at 
all times inhibited by the addition of salts. While all salts 
(including sodium chlorid) showed this behavior some were 
relatively more powerful than others — the bivalent and tri- 
valent radicals being more active, generally speaking, than the 
monovalent ones. 

As previously emphasized, the urinary membrane (the kidney 
itself) is composed, in the main, of a mixture of hydrophilic 
protein colloids which, as we learned, are capable of existing 
in two fairly well-defined states: in a solid or gel state and in 
a liquid or sol state. A familiar illustration of such existence 

*E. von Regeczy: Pfliiger's Arch., 34, 431 (1884). 

2 T. B. Wood and W. B. Hardy: Proc. Roy. Soc. London, Series B, 81, 
38 (1908). 



508 



(EDEMA AND NEPHRITIS 



in two states is offered by ordinary gelatin. Under certain 
conditions this appears in the form of a stiff jelly, under others 
as a " solution." In the same way fibrin represents the gel 
form of the sol fibrinogen, paracasein (casein) the gel of casein 
(caseinogen) , ordinary soft rubber, the gel of a " dissolved " 
rubber, etc. 

It is generally recognized that a rather close relationship 
exists between the gel state in which the colloid is " swelled " 
and the sol state of this same colloid in which it is " dissolved," 
and yet the transition from the one state into the other is not 
necessarily or in all examples a perfectly smooth affair. We 
need only to call attention to the fact that ordinary gelatin, 
for example, when thrown into cold water merely swells up — 
it enters the gel state. But in this state it remains, one might 
say almost indefinitely; to mere appearance it does not go 
into solution at all as would, for example, the crystals of any 
salt thus thrown into the solvent. But if the temperature 
of the water is raised then the gelatin goes into solution rapidly 
— it passes over into the sol state. A change in temperature 
in this case is necessary to accomplish its " solution." As to 
our mind albuminuria represents just such a passage of a colloid 
in the gel state (the proteins of the urinary membrane) over 
into a colloid in the sol state (the proteins contained in the 
urine of the albuminuric individual), let us study the conditions 
favoring such a transition in more detail, paying especial atten- 
tion to such changes in surroundings as we might imagine could 
come into play in the cells of the living animal. Fibrin, gelatin 
and aleuronat 1 have been studied in this regard. The following 
facts regarding fibrin and gelatin are of importance in the further 
development of our subject. 

2. Observations on the " Solution " of Colloid (Protein) Gels 

(a) Fibrin. — When well-washed fibrin that has been thor- 
oughly dried and then powdered in a mortar is thrown into 
water it swells up somewhat. Even though the vessel is thor- 
oughly shaken practically none of the protein goes into solution 
in the water. The matter is easily tested by filtering the water 
off the fibrin and treating the filtrate in any of the accepted ways 

1 Marian 0. Hooker and Martin H. Fischer: Kolloid-Zeitschr., 26, 

49 (1920). 



NEPHRITIS 



509 



for albumin. One must only be careful to use a fine filter or else 
not powder the fibrin so thoroughly that gross particles of it 
can pass through the pores. By similar means it can be shown 
that the fibrin will not dissolve appreciably in any solution of the 
ordinary neutral salts. In a solution of any acid (or alkali) it 
not only swells up more than in water, but it goes into solution. 
Within certain limits more and more fibrin goes into "solution" 
with every increase in the concentration of the acid (or the alkali) . 
But in this matter there seems to exist an optimum above which 
the progressive increase in "solution" stops and gives way to a 
fall. There is, moreover, an upper limit to the total amount of 
fibrin that goes into solution in a given volume of the solvent. 
Under given conditions one has quite as much albumin in " solu- 
tion " after shaking a mixture for two or three hours as after 
two or three days. 

In a given concentration of acid (or alkali) the amount of fibrin 
that " dissolves " is markedly decreased through the addition of 
any neutral salt. With a progressive increase in the concentra- 
tion of the salt there is a progressive decrease in the amount of 
fibrin dissolved. But the character of the salt is not immaterial. 
When equimolar solutions of different salts are compared, some 
act more powerfully than others, but on the basis of my exper- 
iments as thus far carried out it is unsafe to state definitely 
the order in which the various salt radicals affect the " solution " 
of the solid gel. The order seems to be identical with that 
in which they affect the swelling of fibrin. Monovalent radicals 
are, as a group, less powerful in decreasing the " solution " of 
fibrin in an acid (or an alkali) than are bivalent ones, and these 
than trivalent radicals. 

What has been said will be rendered clearer by introducing 
a few typical experiments. Fig. 148 indicates the general way 
in which these experiments were performed. Weighed amounts 
of powdered fibrin were introduced into measured volumes of 
various solutions contained in Erlenmeyer flasks which were 
then placed in a shaking machine and shaken for various periods 
of time. At the expiration of this time the fibrin was allowed 
to settle, and the supernatant liquid was decanted off into a 
filter-lined funnel and received into a second flask. After 
stirring the filtrate, a measured volume was taken and the 
amount of " dissolved " albumin contained in it determined 



510 



(EDEMA AND NEPHRITIS 



quantitatively through precipitation with phosphotungstic acid 1 
and measurement of the heights of the precipitate either in the 
graduated Esbach albuminometer tubes or calibrated test-tubes. 
As the experiments are purely comparative in character I have 
contented myself in these pages with simply photographing the 
results of a few of such as have a direct bearing upon our subject. 





Experiment 68. — 0.5 gram of powdered fibrin was shaken up for 
five hours in each,.of the following solutions : 

1. 50 cc. n/l25HCl 

2. 50 cc. n/80 HC1 

3. 50 cc. n/50 HC1. 

4. 50 cc. n/25 HC1. 

5. 50 cc. n/10 HC1. 

6. 50 cc. H 2 0. 

The appearance of the fibrin in each of the flasks at the end of this 
time is shown in Fig. 148. In the first three flasks (1, 2, 3) there is 
progressive increase in the swelling of the fibrin with the progressive 
increase in the concentration of the acid. Beyond this point (flasks 
4 and 5) there is a decrease in the swelling in spite of the further increase 
in the concentration of the acid. The least amount of swelling is noted 
in flask 6, which contains water only. The solution of the fibrin is 
indicated in Fig. 149. From left to right these tubes correspond with 

1 The phosphotungstic acid reagent had the following composition: 

Phosphotungstic acid, 100 grams. 
Sulphuric acid (sp.gr. 1.84), 100 grams. 
Water enough to make 1000 cc. 



NEPHRITIS 



511 



the flasks of Fig. 148. No precipitate of albumin is seen in the tube 
on the extreme right, indicating that the fibrin did not go into solution 
appreciably in the water (neutral reaction). All the remaining tubes 
show a precipitate of albumin. 




Figure 149. 



Experiment 69.— 0.5 gram of powdered fibrin was put into each of 
the following solutions and shaken for five hours : 

1. 10 cc. n/10 HC1+40 cc. H 2 0. 

2. 10 cc. n/10 HC1+40 cc. m/8 NaCl. 

3. 10 cc. n/10 HC1+40 cc. m/6 NaCl. 

4. 10 cc. n/10 HC1+40 cc, m/4 NaCl. 

5. 50 cc. H 2 0. 

The amount of albumin that went into solution is indicated in 
Fig. 150. No precipitate is seen in the tube on the extreme right 
(water). Most albumin is found in the first tube (pure acid solution). 
It is evident that the presence of the sodium chlorid reduces the 
amount of the albumin that goes into solution. The amount of this 
reduction is the greater the higher the concentration of the salt. 

Experiment 70. — 0.5 gram of powdered fibrin was placed in each of 
four flasks containing the following solutions and shaken for 5 hours: 

1. 10 cc. n/10 HC1+40 cc. H 2 0. 

2. 10 cc. n/10 HC1+40 cc. m/8 Na 2 S0 4 . 

3. 10 cc. n/10 HC1+40 cc. m/8 MgS0 4 . 

4. 10 cc. n/10 HC1+40 cc. m/8 CuS0 4 . 



512 



(EDEMA AND NEPHRITIS 




Figure 151. 



NEPHRITIS 



513 



After filtering, the amount of albumin dissolved in the supernatant 
liquid found above the fibrin in each of the flasks was determined by 
mixing 20 cc. of filtrate with 14 cc. phosphotungstic acid. The result 
is shown in Fig. 151. As is readily apparent, each of the salts markedly 
reduced the amount of albumin that was dissolved. 




Figure 152. 



Experiment 71. — 0.5 gram of powdered fibrin was introduced 
into each of five flasks containing the following solutions and shaken 
for five hours : 

1. 10 cc. n/10 HC1+40 cc. m/8 sodium acetate. 

2. 10 cc. n/10 HC1+40 cc. m/8 sodium nitrate. 

3. 10 cc. n/10 HC1+40 cc. m/8 sodium sulphate. 

4. 10 cc. n/10 HC1+40 cc. m/8 sodium citrate. 

5. 10 cc. n/10 HC1+40 cc. H 2 0. 

The relative amounts of albumin found dissolved in each of these 
mixtures at the end of this time are indicated in Fig. 152. As is 
again evident, most albumin was dissolved by the pure acid solution. 
Each of the salts decreased through its presence the amount thus 
dissolved. 

(b) Gelatin. — What has been said regarding the " solution " 
of fibrin holds almost word for word for the " solution " of gelatin. 
The best commercial gelatin shows some solubility in water. 
When, instead of being placed in water, gelatin is dropped 
into solutions of acids (or alkalies) this solubility of the 



514 



(EDEMA AND NEPHRITIS 



(commercial) gelatin is greatly increased. The presence of 
neutral salts in the acid (or alkali) solution decreases the amount 
of the gelatin that will go into solution. As in the case of fibrin, 
we note here again a progressive decrease in the amount that 
" dissolves " with every increase in the concentration of the 
added salt. With a given concentration the amount of such 
a decrease varies with the salt employed, and here again it seems 
that monovalent salt radicals do not as a group decrease the 
" solubility " of the gelatin as much as bivalent, or these as much 
as trivalent ones. 

The following experiments may serve in illustration of what 
has been said: 

Experiment 72.^The following solutions were prepared: 

1. 100 cc. H 2 0. 

2. 100 cc. n/1000 HC1. 

3. 100 cc. n/500 HC1. 

4. 100 cc. n/200 HC1. 

5. 100 cc. n/100 HC1. 

6. 100 cc. n/75 HC1. 

7. 100 cc. n/50 HC1. 

8. 100 cc. n/40 HC1. 

9. 100 cc. n/30 HQ. 

Five leaves of dry gelatin, each measuring 3| by 1| cm., weigh- 
ing altogether 0.5 gram, and obtained by cutting them out of the 
central portions of the large gelatin leaves that are obtained com- 
mercially, were dropped into each of these solutions. From time to 
time the dishes containing the solutions with their gelatin leaves were 
agitated so as to keep them from adhering to the sides, and aid the 
solution of the gelatin. All the vessels were treated exactly alike. 
The degree of solution of the gelatin after twenty-eight hours in these 
various solutions is indicated in Fig. 153. As the photograph shows, 
least gelatin is dissolved in the pure water. With the increase in the 
concentration of the acid there is a progressive increase in the amount 
of dissolved gelatin, but only up to a certain point, after which it falls 
in spite of the continued further increase in the concentration of the acid. 

Experiment 73. — In the manner just described, 5 leaves of dry 
gelatin, weighing in toto 0.5 gram, and of the same surface were placed 
in each of the following solutions : 

1. 100 cc. H 2 0. 

2. 15 cc. n/10 HC1+85 cc. H 2 0. 

3. 15 cc. n/10 HC1+2| cc. 2/m NaCl+82i cc. H 2 0. 

4. 15 cc. n/10 HC1+ 5 cc. 2/m NaCl+80 cc. H 2 0. 

5. 15 cc. n/10 HC1+10 cc. 2/m NaCl+75 cc. H 2 0. 

6. 15 cc. n/10 HC1+15 cc. 2/m NaCl+70 cc. H 2 0. 



NEPHRITIS 



515 



The relative degrees of solution of the gelatin after a residence in 
these mixtures of eighteen hours is indicated in Fig. 154. The addition 
of the salt has decreased the amount of the gelatin that goes into solu- 
tion in the hydrochloric acid, and this the more the higher the concen- 
tration of the added salt. 



i i l ft i * | i 


i ffi : 


» • 9 ■ 1 1 


ill 


i 

PI 





Figure 153. 



Experiment 74. — Five leaves of dry gelatin weighing altogether 
0.4 gram and having the same surface were placed in each of the fol- 
lowing solutions : 

1. 15 cc. n/10 HC1+85 cc. H 2 0. 

2. 15 cc. n/10 HC1+10 cc. m/1 sodium acetate+75 cc. H 2 0. 

3. 15 cc. n/10 HC1+10 cc. m/1 sodium chlorid +75 cc. H 2 0. 

4. 15 cc. n/10 HC1+10 cc. m/1 sodium nitrate +75 cc. H 2 0. 

5. 15 cc. n/10 HC1+40 cc. m/4 disodium hydrogen phosphate 

+45 cc. H 2 0. 

6. 15 cc. n/10 HC1+40 cc. m/4 sodium sulphate+45 cc. H 2 0. 

7. 15 cc. n/10 HC1+10 cc. m/1 sodium citrate +75 cc. H 2 0. 

The relative amounts of gelatin dissolved in these various solu- 
tions after the gelatin leaves had with occasional agitation remained 
in them for 19^ hours are indicated in Fig. 155. As is readily evident, 
each of the salts decreases by its presence the amount of gelatin dis- 
solved in the acid solution. The bivalent and trivalent acid radicals 
are more powerful in this respect than the monovalent ones, with the 
exception of the acetate. The intermediate position taken by this 
radical, in this matter of the solution of the gelatin, corresponds with 
the intermediate position occupied by this same radical in the swelling 
of the colloid under similar circumstances. 



516 



(EDEMA AND NEPHRITIS 




I villi* ■ 



Figure 155. 



NEPHRITIS 



517 



These experiments show that the " solution " of two typical 
protein colloids is intimately connected with the character 
of the medium surrounding them. Acids (and alkalies) favor 
their solution, while various other substances (notably salts) 
either do not affect it at all, or when present in conjunction 
with an acid (or alkali) depress the amount that would have 
been " dissolved " if the acid (or alkali) had been present 
alone. 

Let us now recall that what lies between the urine on the 
one hand and the blood on the other (the kidney) is made up 
physico-chemically of just such colloid gels as these under dis- 
cussion. Furthermore, we learned above that under normal 
circumstances, in " health," in other words, conditions are 
such in the kidney that this gel state is maintained. But in 
nephritis the acid content of the kidney is increased, in con- 
sequence of which conditions are offered which permit these 
protein colloids to pass over into the sol state and so escape 
with the urine. Albuminuria results whenever some or all of the 
colloid gels that constitute the urinary membrane go into 11 solution " 
in the urine, and this is made possible under the same conditions 
which permit fibrin or gelatin gels to " dissolve " in water. We 
shall find further evidence in support of this belief as we proceed. 

If it is true that albuminuria represents merely a " solution " 
of the kidney proteins in the urine, if, in other words, it does not 
come from the blood (except in that indirect way in which the 
proteins of any cell come originally from the blood), then albu- 
minuria cannot be that strange and specific thing which as clin- 
icians we are likely to think it. Any cell must, under conditions 
similar to those existing in the kidney when this is nephritic, be capable 
of serving as a source of albumin to a surrounding liquid medium, 
and so be capable of being responsible for a state which in the kidney 
goes by the name of " albuminuria^ A little thought will show 
that such actually is the case. 

Every worker in the biological sciences is familiar with the 
ancient fact that " dead " organisms allow the escape of protein 
from them. A frog or fish living in its aquarium does not impart 
a protein reaction to the water. But let it die and in a few 
hours the previously clear water gives a positive result when 
tested for albumin, and this reaction becomes the more intense 
as time goes on. What happens is that after death the tissues 



518 



(EDEMA AND NEPHRITIS 



develop the familiar postmortem acids and under their influence 
some of the proteins now go into " solution " in the surrounding 
medium. Such " solution " occurs whether the organism is a 
simple or complex one. Only when a simple organism possessing 
no circulatory system thus serves as a source of albumin then 
we can no longer talk about a " filtering " off of albumin, an 
" increased permeability of vessel walls/' etc., — as we should 
not in the discussion of the albuminuria of nephritis. 

But we need not wanier so far away from the mammals, 
or in fact the living animal itself, in order to show that " albu- 
minuria " is not the specific thing we think it. As surgeons 
well know, the normal int stinal juices scarcely yield an albumin 
test, yet the fluid contained in a strangulated hernia or a volvulus 
is rich in albumin. Here the interference with the circulation 
to the gut, produced through the strangulation or the twist, 
has placed a section of the bowel in a state of lack of oxygen; 
it develops in consequence an abnormally high acid content, 
and so some of the proteins of the gut wall go into " solution " — 
in other words, we get in the bowel what in the kidney is called 
albuminuria. 

Analogous conditions come to pass in the parenchymatous 
organs. When these are placed under circumstances which lead to 
an increase in their acid content, a state analogous to the albu- 
minuria of the kidney results. The lymph coming from a muscle 
that is made to work hard has a higher albumin content than 
that coming from this same muscle when at rest, and when the 
circulation through the liver is impeded (I would say oxygen supply 
through the hepatic artery is interfered with), either through 
ligation of the inferior vena cava or obturation of the thoracic 
aorta, the albumin content of the lymph coming from this organ 
begins to rise, as E. H. Starling 1 has clearly shown. In glau- 
coma the albumin content of the fluid of the anterior chamber 
rises, and in oedema of the brain and cord the cerebro-spinal 
fluid shows a more than usual amount of protein. 2 

1 E. H. Starling: Jour. Physiol., 16, 224 (1894); 17, 30 (1895); see also 
Bayliss and Starling: ibid., 16, 159 (1894). 

2 Edmund M. Baehr: Personal communication (1913). 



NEPHRITIS 



519 



3. On the Relation between Swelling and Solution in Protein 

Colloids 1 

The importance of the swelling and of the liquefaction or 
" solution" 2 of protein colloids for the interpretation of such bio- 
logical problems as cedema and albuminuria and the fact that 
the same external changes influence both and in the same general 
direction compels inquiry regarding the relation between the two. 

It is a commonly accepted view that the "solution" of a protein 
represents but the extreme of that which in lesser degree is called 
swelling. So far as I know, it has been held almost universally 
that sufficient hydration results as a matter of course in "solution." 
Careful investigation of the problem, however, shows that this is 
not the case. The matter is easily proved by working with such a 
protein as gelatin at concentrations and temperatures near its 
gelation or melting point. Since acids and alkalies increase hydra- 
tion, the addition of these substances to a barely liquid gela- 
tin-water mixture ought to stiffen it. As a matter of fact just the 
reverse occurs. By working instead with a stiff gelatin, a pre- 
viously solid mixture is made to liquefy upon the addition of these 
substances. The ■ phenomena of swelling (hydration) and of "solu- 
tion" in protein gels while frequently associated are therefore essen- 
tially different. Swelling is best understood as a change whereby the 
protein enters into physico-chemical combination with more of the 
solvent (water), as a change in the direction of greater solubility of the 
solvent in the protein; "solution" is best conceived of as a change 
in the direction of greater solubility (an increased degree of disper- 
sion) of the colloid in the solvent. If reference is made to Fig. 3 
(page 56) it will be noted that changes involving swelling occur 
in the region below the level marked V; changes in the direction of 
liquefaction or " solution " above the level marked E. 



The experiments which seem to justify these deductions were 
carried out as follows. A high grade commercial gelatin low in 

1 Martin H. Fischer: Science, 42, 223 (1915); Kolloid-Zeitschr., 17, 
1 (1915). 

2 Since there are many minds regarding the nature of solution, accurate 
definition of the term is not easy. I am here using the term in its broadest 
sense as covering everything, in the case of the colloids, from their liquefac- 
tion point upwards to the accepted "true" solution of the physical chemists. 




§ i 



520 



(EDEMA AND NEPHRITIS 



salts was used and one which previous experiments had shown to 
be capable of setting into a firm jelly at very low concentrations. 
From this there was prepared a homogeneous 10 per cent stock 
solution which was then used in the various series of experiments. 
After having once obtained this stock, all unnecessary further 
heating of the gelatin was avoided. To prepare the various 
gelatin mixtures the stock gelatin was warmed to slightly above 
its liquefaction point and, after mixing with the necessary reagents 
in test tubes of uniform diameter, the mixtures were all reduced to 
the temperature of 25° C. as rapidly as possible and kept there. 
Precautions were taken to treat every set of tubes in each of the 
series of experiments exactly alike so far as methods of mixing, 
exposure to changes in temperature, etc., were concerned. 

An 0.8 to 0.9 per cent solution of the stock gelatin would set 
into a solid mass, permitting the test tube to be turned over with- 
out having the contents flow, when left to itself for a few hours at 
25° C. It having been determined in this fashion that any gelatin- 
water mixture above a 1 per cent concentration of this gelatin 
would remain solid, the following Experiment 75 with a 2 per cent 
gelatin was carried out in order to discover whether the addition 
of acid to the gelatin would increase or decrease its tendency to 
gel. Since acids increase the power of protein colloids to swell 
(and increase the viscosity of gelatin sols) it was to be expected, on 
a priori grounds, that the addition of acid would tend to increase 
the tendency of gelatin to gel. As the following shows, the addition 
of acid very markedly decreases the tendency of gelatin to gel (increases 
its tendency to " dissolve "). 

Experiment 75. — 

1. 2 cc. 10% gelatin +8 cc. H 2 0. 

2. 2 cc. 10% gelatin+0.1 cc. n/10 HC1+7.9 cc. H 2 0. 

3. 2 cc. 10% gelatin +0.2 cc. n/10 HC1+7.8 cc. H 2 0. 

4. 2 cc. 10% gelatin +0.3 cc. n/10 HC1+7.7 cc. H 2 0. 

5. 2 cc. 10% gelatin +0.4 cc. n/10 HC1+7.6 cc. H 2 0. 

6. 2 cc. 10% gelatin +0.5 cc. n/10 HC1+7.5 cc. H 2 0. 

7. 2 cc. 10% gelatin + 1.0 cc. n/10 HC1+7.0 cc. H 2 0. 

8. 2 cc. 10% gelatin +1.5 cc. n/10 HC1+6.5 cc. H 2 0. 

9. 2 cc. 10% gelatin +2.0 cc. n/10 HC1+6.0 cc. H 2 0. 

10. 2 cc. 10% gelatin +2.5 cc. n/10 HC1+5.5 cc. H 2 0. 

11. 2 cc. 10% gelatin +3.0 cc. n/10 HC1+5.0 cc. H 2 0. 

After these mixtures had stood for twenty-four hours the control gela- 
tin mixture in tube 1 was perfectly solid. The mixtures in tubes 2, 3, 4, 



NEPHRITIS 



521 



5 and 6 were so solid that they could be turned over, though on hard 
shaking the surfaces in the two last named could be made to quiver. 
In tube 7 the gelatin flowed as a viscid liquid. In tubes 8, 9, 10 and 11 
the mixtures were entirely fluid. 

Just as the presence of acid liquefies gelatin so does that of 
alkali. This is shown in Experiment 76. 

Experiment 76. 

1. 2 cc. 10% gelatin +8 cc. H 2 0. 

2. 2 cc. 10% gelatin +0.1 cc. n/10 NaOH+7.9 cc. H 2 0. 

3. 2 cc. 10% gelatin +0.2 cc. n/10 NaOH+7.8 cc. H 2 0. 

4. 2 Cc. 10% gelatin +0.3 cc. n/10 NaOH+7.7 cc. H 2 0. 

5. 2 cc. 10% gelatin +0.4 cc. n/10 NaOH+7.6 cc. H 2 0. 

6. 2 cc. 10% gelatin +0.5 cc. n/10 NaOH+7.5 cc. H 2 0. 

7. 2 cc. 10% gelatin +1.0 cc. n/10 NaOH+7.0 cc. H 2 0. 

8. 2 cc. 10% gelatin +1.5 cc. n/10 NaOH+6.5 cc. H 2 0. 

9. 2 cc. 10% gelatin +2.0 cc. n/10 NaOH+6.0 cc. H 2 0. 

10. 2 cc. 10% gelatin +2.5 cc. n/10 NaOH+5.5 cc. H 2 0. 

11. 2 cc. 10% gelatin +3.0 cc. n/10 NaOH+5.0 cc. H 2 0. 

After standing for twenty-four hours at 25° C. the gelatin in tube 1 
was solid; that in tubes 2, 3, 4 and 5 was also solid; in tube 6 the surface 
quivered on shaking. The gelatin in tube 7 flowed as a viscid liquid. In 
the remaining tubes the gelatin was entirely liquid. 

To show that the presence of acid or alkali will not only 
prevent the gelation of gelatin, but that it will liquefy this after 
gelation has occurred, Experiment 77 is introduced. 

Experiment 77. — 

1. 2 cc. 10% gelatin +8 cc. H 2 0. 

2. 2 cc. 10% gelatin +0.3 cc. n/10 HC1+7.7 cc. H 2 0. 

3. 2 cc. 10% gelatin +0.5 cc. n/10 HC1+7.5 cc. H 2 0. 

4. 2 cc. 10% gelatin +1.0 cc. n/10 HC1+7.0 cc. H 2 0. * 

5. 2 cc. 10% o gelatin +2.0 cc. n/10 HC1+6.0 cc. H 2 0. 

6. 2 cc. 10% gelatin +3.0 cc. n/10 HC1+5.0 cc. H 2 0. 

7. 2 cc. 10% gelatin +8 cc. H 2 0. 

8. 2 cc. 10% gelatin +0.3 cc. n/10 NaOH+7.7 cc. H 2 0. 

9. 2 cc. 10% gelatin +0.5 cc. n/10 NaOH+7.5 cc. H 2 0. 

10. 2 cc. 10% gelatin +1.0 cc. n/10 NaOH+7.0 cc. H 2 0. 

11. 2 cc. 10% gelatin +2.0 cc. n/10 NaOH+6.0 cc. H 2 0. 

12. 2 cc. 10% gelatin +3.0 cc. n/10 NaOH+5.0 cc. H 2 0. 

In this series the gelatin and water were first mixed and, at the end of 
twenty-four hours when the gelatin mixtures had solidified, the acid or 
alkali was dropped upon them. At the end of the second twenty-four 
hours the following was observed. Control tubes 1 and 7 containing only 



522 



(EDEMA AND NEPHRITIS 



pure gelatin were solid. Decrease in viscosity to complete liquefaction of 
the gelatin was observable in the remaining tubes. As more than twenty- 
four hours is required for the acid to diffuse through the entire depth of the 
gelatin, the upper portions of the gelatin columns showed the greatest 
amount of change. In tubes 2 and 3 and tubes 8 and 9 there was a distinct 
softening of the upper portions of the gelatin column. The upper half of 
tubes 4 and 10 flowed as a viscid liquid. In tubes 5 and 6 and tubes 11 
and 12 the gelatin was liquefied almost to the bottom of the tubes. 

Since different salts decrease the tendency of various proteins 
to swell in the presence of an acid or an alkali it was to be expected 
that their addition to an acid or alkali-gelatin mixture should 
liquefy further such a mixture provided swelling and solution were 
identical processes. Experiment 78 shows again that just the 
opposite occurs. The addition of sodium chlorid tends to counter- 
act the liquefying effect of an acid. 

Experiment 78. 



1. 2 cc. 10% gelatin +8 cc. H 2 0. 

2. 2 cc. 10% gelatin + 1.5 cc. n/10 HC1+6.5 cc. H 2 0. 



3. 2 cc. 


10% 


gelatin + 1.5 


cc. 


n/10 


HC1+0.1 


cc. 


m/1 


NaCl 


+6.4 cc. H 2 0. 


















4. 2 cc. 


10% 


gelatin + 1.5 


cc. 


n/10 


HC1+0.2 


cc. 


m/1 


NaCl 


+6.3 cc. H 2 0. 


















5. 2 cc. 


10% 


gelatin + 1.5 


cc. 


n/10 


HC1+0.3 


cc. 


m/1 


NaCl 


+6.2 cc. H 2 0. 


















6. 2 cc. 


10% 


gelatin +1.5 


cc. 


n/10 


HC1+0.4 


cc. 


m/1 


NaCl 


+6.1 cc. H 2 0. 


















7. 2 cc. 


10% 


gelatin + 1.5 


cc. 


n/10 


HC1+0.5 


cc. 


m/1 


NaCl 


+6.0 cc. H 2 0. 


















8. 2 cc. 


10% 


gelatin + 1.5 


cc. 


n/10 


HC1 + 1.0 


cc. 


m/1 


NaCl 


+5.5 cc. H 2 0. 


















9. 2 cc._ 


10% 


gelatin + 1.5 


cc. 


n/10 


HC1+2.0 


cc. 


m/1 


NaCl 


+4.5 cc. H 2 0~ 


















10. 2 cc. 


10% 


gelatin + 1.5 


cc. 


n/10 


HC1+3.0 


cc. 


m/1 


NaCl 


+3.5 cc. H 2 0. 


















11. 2 cc. 


10% 


gelatin + 1.5 


cc. 


n/10 


HC1+4.0 


cc. 


m/1 


NaCl 


+2.5 cc. H 2 0. 


















12. 2 cc. 


10% 


gelatin + 1.5 


cc. 


n/10 


HC1+5.0 


cc. 


m/1 


NaCl 



+ 1.5 cc. H 2 0. 

Twenty-four hours after the mixtures had been prepared the pure 
gelatin in tube 1 was solid; the acidified gelatin in tube 2 was liquid. A 
distinct influence of the sodium chlorid in inhibiting the solvent action of 
the acid was evident even in tube 3 where the mixture barely flowed. 
The viscosity increased progressively from tubes 4 to 7 in which the opti- 
mum effect of the sodium chlorid in restraining liquefaction was observed. 



NEPHRITIS 



523 



Here the gelatin was solid, but not quite so solid as the pure gelatin. The 
gelatin mixtures in tubes 8, 9 10, 11 and 12 were solid, but on tapping 
quivered more easily than did the gelatin in tube 7. 

Experiment 79, similar in arrangement to Experiment 78, 
brings out the same facts for an alkali-gelatin series. Sodium 
chlorid inhibits the liquefying action of sodium hydroxid as it 
did that of acid. 

Experiment 79. 

1. 2 cc. 10% gelatin+8 cc. H 2 0. 

2. 2 cc. 10% gelatin +1.5 cc. n/10 NaOH+6.5 cc. H 2 0. 



3 2 cc 10% 


gelatin +1.5 


cc. 


n/10 


NaOH-4-0 1 


cc. 


m/1 


NaCl 


+6.4 cc. H 2 0. 
















4. 2 cc. 10% 


gelatin +1.5 


cc. 


n/10 


NaOH+0.2 


cc. 


m/1 


NaCl 


+6.3 cc. H 2 0. 
















5. 2 cc. 10% 


gelatin + 1.5 


cc. 


n/10 


NaOH+0.3 


cc. 


m/1 


NaCl 


+6.2 cc. H 2 0. 
















6. 2 cc. 10% 


gelatin +1.5 


cc. 


n/10 


NaOH+0.4 


cc. 


m/1 


NaCl * 


+6.1 cc. H 2 0. 
















7. 2 cc. 10% 


gelatin +1.5 


cc. 


n/10 


NaOH+0.5 


cc. 


m/1 


NaCl 


+6.0 cc. H 2 0. 
















8. 2 cc. 10% 


gelatin +1.5 


cc. 


n/10 


NaOH + 1.0 


cc. 


m/1 


NaCl 


+5.5 cc. H 2 0. 
















9. 2 cc. 10% 


gelatin + 1.5 


cc. 


n/10 


NaOH+2.0 


cc. 


m/1 


NaCl 


+4.5 cc. H 2 0. 
















10. 2 cc. 10% 


gelatin + 1.5 


cc. 


n/10 


NaOH+3.0 


cc 


m/1 


NaCl 


+3.5 cc. H 2 0. 
















11. 2 cc. 10% 


gelatin + 1.5 


cc. 


n/10 


NaOH+4.0 


cc. 


m/1 


NaCl 


+2:5 cc. H 2 0. 
















12. 2 cc. 10% 


gelatin + 1.5 


cc. 


n/10 


NaOH+5.0 


cc. 


m/1 


NaCl 



+1.5 cc. H 2 0. 



At the end of twenty-four hours the pure gelatin was solid; the gelatin 
plus the alkali was liquid. The tubes containing sodium chlorid in addi- 
tion were all solid, the optimum effect of the salt again being evident in 
tube 7. 

Sodium chlorid antagonizes the liquefying action of acid only 
when the latter is not present in too high concentration. In 
other words, with a given concentration of sodium chlorid an in- 
crease in the acid content will again serve to liquefy the gelatin. 
This is shown in Experiment 80, in which different amounts of 
acid are added to a gelatin-salt mixture of constant concentra- 
tion. 



524 



(EDEMA AND NEPHRITIS 



Experiment 80. 

1. 2 cc. 10% gelatin +8 cc. H 2 0. 

2. 2 cc. 10% gelatin + 1 cc. m/1 NaCl+7 cc. H 2 0. . 

3. 2cc. 10% gelatin + 1 cc. m/1 NaCl + 1.0 cc. n/10 HC1 
+6 ce. H 2 0. 

4. 2 cc. 10% gelatin +1 cc. m/1 NaCl+1.5 cc. n/10 HC1 
+5.5 cc. H 2 0. 

5. 2 cc. 10% gelatin + 1 cc. m/1 NaCl+2.0 cc. n/10 HC1 
+5.0 cc. H 2 0. 

6. 2 cc. 10% gelatin + 1 cc. m/1 NaCl+2.5 cc. n/10 HC1 
+4.5 cc. H 2 0. 

■7. 2 cc. 10% gelatin + 1 cc. m/1 NaCl+3.0 cc. n/10 HC1 
+4.0 cc. H 2 0. 

8. 2 cc. 10% gelatin+1 cc. m/1 NaCl+3.5 cc. n/10 HC1 
+3.5 cc. H 2 0. . 

9. 2 cc. 10% gelatin + 1 cc. m/1 NaCl+4.0 cc. n/10 HC1 
+3.0 cc. H 2 0. 

10. 2 cc. 10% gelatin+1 cc. m/1 NaCl+4.5 cc. n/10 HC1 
+2.5 cc. H 2 0. 

11.2 cc. 10% gelatin+1 cc. m/1 NaCl+5.0 cc. n/10 HC1 
+2.0 cc. H 2 0. 

At the end of twenty-four hours the pure gelatin in tube 1 was solid as 
was also the pure sodium chlorid-gelatin mixture in tube 2. Tube 3 con- 
tained an amount of acid which, as shown in Experiment 75, was able to 
keep gelatin from solidifying. In the presence of sodium chlorid, however, 
this gelatin mixture was found to be solid. The liquefying action of the 
acid concentrations in tubes 4 and 5 was also so restrained by the chlorid 
that in these the gelatin merely quivered on tapping. In tubes 6 and 7 the 
gelatin almost flowed, and in tubes 8, 9, 10 and 11 it did this in progressing 
degree. 

Experiment 81 shows the' effect of a salt with a bivalent 
acid radical, Experiment 82 of one with a bivalent basic radical. 

Experiment 81. 

1. 2 cc. 10% gelatin +8 cc. H 2 0. 

2. 2 cc. 10% gelatin +1.5 cc. n/10 HC1+6.5 cc. H 2 0. 

3. 2 cc. 10% gelatin + 1.5 cc. n/10 HC1+0.4 cc. m/1 Na 2 S0 4 
+6.1 cc. H 2 0. 

4. 2 cc. 10% gelatin + 1.5 cc. n/10 HC1+0.8 cc. m/1 Na 2 S0 4 
+5.7 cc. H 2 0. 

5. 2 cc. 10% gelatin + 1.5 cc. n/10 HC1+1.2 cc. m/1 Na 2 S0 4 
+5.3 cc. H 2 0. 

6. 2 cc. 10% gelatin + 1.5 cc. n/10 HC1+2.0 cc. m/1 Na 2 S0 4 
+4.5 cc. H 2 0. 

7. 2 cc. 10% gelatin + 1.5 cc. n/10 HC1+4.0 cc. m/1 Na 2 S0 4 
+2.5 cc. H 2 0. 



NEPHRITIS 



525 



Twenty-four hours later the gelatin in tube 1 was solid; in tubes 2 and 
3 liquid; in tube 4 the contents were viscid; tube 5 could be turned over; 
the gelatin tubes 6 and 7 were solid. 

Experiment 82. 

1. 2 cc. 10% gelatin +8 cc. H 2 0. 

2. 2 cc. 10% gelatin +1.5 cc. n/10 HC1+6.5 cc. H 2 0. 

3. 2 cc. 10% gelatin +1.5 cc. n/10 HC1+0.1 cc. m/1 CaCl 2 +6.4 cc. 
H 2 0. 

4. 2 cc. 10% gelatin + 1.5 cc. n/10 HC1+0.2 cc. m/1 CaCl 2 +6.3 cc. 
H 2 0. 

5. 2 cc. 10% gelatin + 1.5 cc. n/10 HC1+0.3 cc. m/1 CaCl 2 +6.2 cc. 
H 2 0. 

6. 2 cc. 10% gelatin + 1.5 cc. n/10 HC1+0.5 cc. m/1 CaCl 2 +6.0 cc. 
H 2 0. 

7. 2 cc. 10% gelatin + 1.5 cc. n/10 HC1 + 1.0 cc. m/1 CaCl 2 +5.5 cc. 
H 2 0. 

8. 2 cc. 10% gelatin + 1.5 cc. n/10 HC1 + 1.5 cc. m/1 CaCl 2 +5.0 cc. 
H 2 0. 

9. 2 cc. 10% gelatin + 1.5 cc. n/10 HC1+2.0 cc. m/1 CaCl 2 +4.5 cc. 
H 2 0. 

10. 2 cc. 10% gelatin + 1.5 cc. n/10 HC1+2.5 cc. m/1 CaCl 2 +4.0 cc. 
H 2 0. 

After twenty-four hours the pure gelatin in tube 1 was solid; that con- 
taining acid in tube 2 liquid; the mixtures in tubes 3 and 4 were viscid; 
in tube 5, almost solid; in tube 7, entirely solid. Beyond this concentra- 
tion the stiffness of the gelatin mixtures again decreased until that in tube 
10 was again liquid. 

In order not to drag out these detailed observations to unneces- 
sary lengths it may be said that, in general, all salts act upon an 
acidified or alkalinized gelatin. There exist, however, certain 
quantitative and qualitative differences when different salts are 
employed. When salts with a common base but different acid 
radicals are compared, it is found that chlorids, bromids, nitrates, 
iodids and sulphocyanates produce about equal effects; acetates 
and sulphates hold a middle position while citrates and tartrates 
are most powerful. On the other hand, with a common acid radical 
the monovalent salts are less powerful than the bivalent, and these 
than the trivalent. How these findings may be understood is 
indicated in the next paragraph. 

§ 2 

The above experiments show that the swelling of a hydrophilic 
colloid like gelatin and its liquefaction or solution while frequently 



525 



(EDEMA AND NEPHRITIS 



associated processes are in essence distinct in character. An 
attempt made earlier 1 to explain what happens in these proteins 
we think no longer adequate. The answer to what seems really to 
happen appears in some later studies on the colloid chemistry of 
soaps. 2 

We now hold to the view that protein, regarded in its simplest 
form as a polymerized amino-acid, behaves colloid-chemically like 
the ordinary fatty acids which in combination with different bases 
form the various soaps. Each of these soaps or soap-like com- 
pounds has its own capacity for taking up water (swelling) and 
solubility in water. Speaking generally, the soaps of the alkali 
metals have the greatest capacity for taking up water and the 
greatest solubility in water. The soaps of the alkaline earths 
occupy a middle position while the soaps of the heavier metals 
take up but little water and are scarcely soluble in water. The 
same is true for the metal proteinates. 

While the fatty acids are capable of combining only with bases 
the amino (fatty) acids, as found in protein, may thus combine not 
only with bases but with acid. This gives a second series of pro- 
tein salts which, dependent upon the kind of acid introduced in the 
protein, yield protein hydrochlorid, protein sulphate, etc. Each 
of these protein compounds has again its characteristic solvent powers 
for water and solubility in water. 

If the above facts are kept in mind, all of the hydration and 
solubility characteristics of gelatin or any other protein are easily 
understood. As we vary in a protein-water system the concentra- 
tion or kind of acid, alkali or salt we form different basic and 
acidic derivatives of the original protein (amino-acid) and the 
swelling and solubility characteristics of the system are an expres- 
sion of the character of these fundamental compounds. 

This first and fundamental chemical arrangement within the 
mixture of the protein salt molecules is, however, not sufficient 
to explain all the changes observed in such systems as have been 
described. The characteristic features of what happens when- 
ever gelatin, acid and salt or gelatin, alkali and salt are mixed 
together is well shown in Experiments 78 and 79. With increas- 

1 Martin H. Fischer: Kolloid-Zeitschr., 27, 5 (1915). 

2 Marian O. Hooker and Martin H. Fischer: Chem. Engineer, 27, 
159, 223, 253 (1919); Martin H. Fischer: Chem. Engineer, 27, 184, 271 
(1915). A running account appears in Soaps and Proteins, New York (1920), 

in press. 



NEPHRITIS 



527 



ing concentration of the added salt to an acid or alkali gelatin 
there is observed, first, an increase in viscosity, resulting later in 
solidification, followed by a secondary fall in viscosity or liquefac- 
tion which, when enough salt is added, ends in a separation of 
the protein in practically anhydrous fashion from the mixture. 
These changes follow even when the salt is so chosen as to preclude 
the possibilities of chemical reaction with the protein compound. 
To understand what happens under such circumstances it is well 
to emphasize the parallelism existing between these changes in 
proteins and those observed in the salting-out of soap. 1 

If we attempt to explain the successive changes which follow 
the addition of a salt to the acid or alkali protein and try to do this 
without recourse to too many violent assumptions the following 
seems the simplest way out. 

The entire series of changes observed in the salting-out of an acid or 
alkali protein by a salt is readily understood if it is assumed that the 
added neutral salt unites with the solvent to form a hydrate or solvate 
and that the consequent viscosity changes (including gelation) are 
those dependent upon the changes in viscosity observed whenever any 
one liquid is emulsified in a second. It does not matter for our 
purposes whether such union with the ' 'solvent" is brought about 
by the molecules or the ions or any other derivatives of the salt. 
The solvates (hydrates) after being formed then separate out in dis- 
persed form in the acid or alkali protein. 

Diagrammatically the successive changes are illustrated in Fig. 
156. If, to simplify matters, we represent the original pure acid 
or alkali protein " solution " as a homogeneous system 2 as indi- 
cated in tube A of Fig. 156, the effect of adding some molecules of 
salt may be represented by the diagram marked B. Hydration of 
the salt molecules has two effects, (1) it withdraws water from the 
original acid or alkali protein system and thus through increase in 
the concentration of the acid or alkali protein tends to stiffen 
the system. But this effect is probably not large as compared 
with (2) the effects upon viscosity of the dispersion of one material 
in a second. The increase in viscosity due to such subdivision of 
one material in a second is observed under widely varying circum- 

1 Martin H. Fischer: Science, 49, 616 (1919); Chem. Engineer, 27, 257 
(1919). 

2 It is at least a di-phasic system, as emphasized in Chem. Engineer, 27, 
184 (1919), but for our purposes we will call it a mono-phasic one. 



528 



(EDEMA AND NEPHRITIS 




NEPHRITIS 



529 



stances. A good example for our purposes is that represented by 
the increase in viscosity when one liquid (like cottonseed oil) is 
emulsified in a second (like a soap solution). The " mayonnaise' 7 
which results may become so stiff that it will stand alone. 

The viscosity of such di-phasic systems — and it is well for our 
purposes to bear in mind particularly di-phasic systems con- 
sisting of one liquid dispersed in a second or of a solid dispersed in a 
liquid — increases with every increase in the concentration of the 
internal dispersed phase and with every decrease in the size of the 
individual dispersed particles. The viscosity of an emulsion of 
liquid oil in liquid soap,, for instance, increases as more and more 
oil is beaten into the soap; or, on the other hand, with a given 
amount of oil subdivided into a given volume of soap the viscosity 
of the mixture is increased if a previously coarse emulsion is made 
more fine by " homogenizing." 

It is such increase in the number of hydrated salt particles 
with increasing concentration of the added salt that explains the 
progressive increase in the viscosity (see diagram C) which, when 
the amount of water in the system is not too high, culminates in 
gelation. If the concentration of the salt is still further increased, 
the time approaches when the number (or size) of the hydrated 
salt particles becomes so great that they touch each other (dia- 
gram D). When this happens a critical point has been reached 
and there must appear a change in the type of the system, for the 
hydrated salt particles now become the continuous external phase 
while the acid or alkali protein particles form the internal divided 
phase. Such change in type of emulsion even without change 
in the quantitative relationships of the two liquids composing the 
emulsion is regularly followed by a change in viscosity. This 
situation is indicated in tube E of Fig. 156. The viscosity of the 
system now tends in the direction of the salt solution and so, with 
further additions of salt, falls. This is the region of secondary 
liquefaction after the region of gelation in our experiments. At 
this point, however, the acid or alkali protein system also shows 
the first evidences of becoming turbid. This is because more 
and more water has been taken from the protein and as this 
becomes dehydrated its index of refraction changes. Being dif- 
ferent from that of the dispersion medium the mixture appears 
milky. The dehydrated acid or alkali protein particles being 
possessed of a lower specific gravity than that of the salt solution 



530 



(EDEMA AND NEPHRITIS 



constituting the dispersion medium begin to float to the top as 
indicated over F in Fig. 156. When enough salt has been added 
to the system, the protein is entirely dehydrated, as shown in 
diagram G. 

4. Critical Remarks 

It has been argued by some of my critics that the "solution" 
theory of albuminuria fails because the amounts of albumin given 
off by a kidney may be so large that were it all due to solution 
the whole kidney would be lost in a short time. Before this 
plausible objection is accepted it is well to consider the following 
rather obvious facts. In the first place, the albuminuria which 
we are discussing and the mechanism of which is a matter of 
debate is only that which is observed even though the blood vessels 
are intact. No one questions the vascular origin of the protein 
derived from frankly ruptured and oozing blood vessels or 
from red and white blood corpuscles which have escaped through 
the substance of the kidney into the urine and died there (dia- 
pedesis with subsequent " solution " of the escaped cells). 

We are likely to find the largest amounts of albumin without 
gross blood vessel lesions in the earlier stages of the acute types 
of nephritis, say in the pregnancy or other toxic nephri tides. 
Suppose we choose a figure high enough to suit everybody and 
say that 20 grams of albumin are being given off to the liter of 
urine. Such kidneys are not likely to be secreting more than 
100 or 200 cc, but suppose they are putting out 500. Even so, 
only 10 grams of albumin are being lost daily and we have 300 or 
more grams of kidney tissue to work on. But such albuminurias 
are neither common nor do they last long — the patient either 
gets over them in a very few days or dies. 

In the chronic types of nephritis we encounter no such figures. 
But even those that are observed cannot without revision be 
credited to that essential albuminuria which alone needs dis- 
cussion. Thus, in chronic interstitial nephritis associated with 
vascular disease the blood vessels in the kidney commonly 
rupture and bleed as they do elsewhere in the body; hemorrhage 
by diapedesis occurs in all types of kidney disease; and leucocytes 
not infrequently wander into the kidney tissues and through 
them into the urine. If the urine has not the right salt concen- 
tration, or is a little too acid or alkaline, all these cellular elements 



NEPHRITIS 



531 



are destroyed and the dissolved protein from this source is added 
to the exuded blood plasma, and both together are added to that 
derived from solution of the kidney itself. In this way the latter 
figure may be pushed to any height, but to say that such an 
amount of albumin has come from the kidney itself may suit a 
critic, but it is wrong. Aside from the fact that if a patient 
lost a gram of protein daily it would take months to destroy 
enough of his kidney substance to make him aware of it, this 
presupposes that a kidney has no regenerative powers, which, 
as a matter of fact, it has equally with other parenchymatous 
organs. A testicle, for instance, produces enough sperm daily 
to total several times its own weight in a year, and yet at the end 
of that time it has not disappeared. 

We need in this place to consider also an editorial criticism 
of the Journal of the American Medical Association. 1 Its head- 
ing " A Controverted Theory of Nephritis " has been chosen 
a little broadly, for the paragraph itself comments only on 
the work of G. Salus, 2 who in connection with his serological 
studies touches on the solution theory of albuminuria. Salus 
found that he could develop a precipitin for human blood serum 
by using albuminous urine as an antigen. He concludes cor- 
rectly from this, that the albumin in his urines contained blood 
proteins. But then no one has ever disputed this fact, for hem- 
orrhage through gross rupture of the blood vessels and by dia- 
pedesis is common in all types of nephritis. 

On the other hand, he found that he could get no response 
(more accurately stated, but one in ten trials) when he added 
the antiserum prepared from albuminous urine to a solution of 
tissue proteins extracted from the kidney. He cites this as evi- 
dence against the presence of dissolved kidney protein in the 
urine. In the face of the fact that it is difficult to prepare a 
specific antiserum even when kidney substance is used directly, 
such findings are hardly conclusive. The colloid chemists, more- 
over, know how alterable in consequence of mere laboratory 
handling are the reactions of proteins, and so some argument 
will be necessary to make those of solid organs and of organ 
extracts synonymous in their minds. Salus himself recognizes 
these difficulties but the editorial writer seems unaware of them. 

Editorial: Jour. Am. Med. Assoc., 62, 1971 (1914). 
2 G. Salus: Biochem. Zeitschr., 60, 1 (1914), 



532 



(EDEMA AND NEPHRITIS 



VI 

THE MORPHOLOGICAL CHANGES IN THE KIDNEY 
1. Introduction 

Anyone who has on the one hand busied himself with the 
clinical, or as we might better say, the biochemical, aspects 
of nephritis, on the other with the . morphological aspects of 
this same problem, as this has been developed for us during 
the last two or three decades, must be struck by the fact that the 
two have not alone grown up practically independently of each 
other, but that they have made but slight effort to find common 
ground. 

As a matter of fact, when we attempt to find a connection 
between the comparatively simple biochemical characteristics of 
nephritis and the elaborate morphological analyses of the organs 
from patients who have clinically shown the biochemical marks 
of a« nephritis, this is at first sight not easy. Even if we ignore 
the fact that much of that which is supposed to characterize 
nephritis morphologically has nothing to do with the albuminuria, 
the changes in the secretion of water, the changes in the secre- 
tion of dissolved substances, etc., which are the distinguishing 
marks of a nephritis biochemically, there still remains an apparent 
lack of connection between the facts, to which any clinician or 
pathologist will testify, namely, that individuals may die of an 
acute Bright' s disease and show surprisingly little macroscopic 
or microscopic change in the kidney, while others, never affected 
with any symptoms referable to the urinary s3 T stem, may show 
on autopsy the infant-sized kidneys of chronic interstitial nephritis. 
And yet if we will but free our minds from the erroneous con- 
clusions to which the temptations of elaborate fixing and stain- 
ing methods and high power microscopes have led us, it is an 
easy matter to see that all the morphological changes that occur 
in a kidney, the seat of an acute or chronic nephritis, are fun- 
damentally simple in character, and that they are easily brought 
into connection with the clinical manifestations of the disease. 
We will discover at the same time that the essential morpholog- 
ical changes of acute and chronic nephritis were recognized and 
a satisfactory classification of the nephri tides on morphological 



NEPHRITIS 



533 



grounds was made decades ago, more especially by Weigert, 1 
and that a classification of the nephritides on the basis of patholog- 
ical physiology brings us in these modern days back to yet older 
teachings, to those of F. T. Frerichs, 2 for example, who regarded 
all the nephritides to be in essence the same. 

2. Classification of the Nephritides. Correlation of the Mor- 
phological Changes in the Kidneys with Some Clinical 
Manifestations 

There is but one kind of nephritis — parenchymatous nephritis. 
How could there be any other? It is the function of the kidney 
to yield a secretion which we call urine, and this function is 
exhibited by the parenchyma of which the kidney is composed. 
A disturbed kidney function can come to pass only as the 
parenchyma has been involved. Histological examination shows 
that the parenchyma is not everywhere the same, and it is pre- 
sumable therefore that the different parts play different roles, 
but since the physiologists have not yet settled what are these 
differences in the functions of the glomeruli, the convoluted 
tubules, the collecting tubules, etc., a more detailed classifica- 
tion into glomerular, tubular, etc., types is, to say the least, 
premature. We know not a single experimental procedure or 
pathological process which involves exclusively only one of these 
structures, and we cannot in consequence do more than speculate 
on their function. 

It is evident that a pathological process may involve a whole 
kidney, in which case we may speak of a generalized parenchy- 
matous nephritis, or it may involve only smaller or larger patches, 
leaving healthy kidney between, in which case we may speak 
of a focal or spotty parenchymatous nephritis. Either of these 
types may, of course, be acute or chronic. If the agencies attack- 
ing the kidney are removed, and if the damage done the paren- 
chyma has not been too great, then, evidently, the involved 
cells may recover, in other words, the normal state of the kidney 
be re-established. Expressed more technically, recovery occurs 
if the changes induced in the kidney remain of a reversible 

1 The most accessible of Weigert's papers on nephritis appear in Vir- 
chow's Archiv during the years 1860 to 1875. 

2 F. T. Frerichs : Die Bright'sche Nierenkrankheit, Braunschweig (1851) . 



534 



(EDEMA AND NEPHRITIS 



type. But if for any reason, say through prolonged or par- 
ticularly intense action of the agencies producing the nephritis, 
irreversible changes occur in the kidney parenchyma, then the 
involved cells die and are absorbed. If the defect is not or can- 
not be made good by regeneration of new cells, then that portion 
of the kidney is gone and in its place may appear nothing more 
than a little scar tissue. All these possibilities of injury with 
recovery, or injury with death and loss of the involved part may 
and do occur in nephritis whether it involves a whole kidney 
or only a patch in it. 

Let us consider first the generalized parenchymatous type of" 
nephritis consequent, say, upon an acute intoxication of some 
kind. It is possible, first of all, for such a kidney to recover 
entirely. But if such a fortunate ending is not attained, death 
of the whole kidney is not the only alternative. Larger 
or smaller pieces may die and be replaced by connective tissue 
while the remainder of the kidney recovers. There will ultimately 
result then a kidney which as far as it goes contains normal 
parenchyma, but in diminished amount, a so-called secondarily 
contracted or sclerosed kidney, a so-called chronic interstitial nephritis - 
secondary to generalized parenchymatous nephritis, the " small 
red kidney " of the pathologists. Diagrammatically represented, 
the process may be illustrated by reference to Fig. 157. The 
rather uniform effect of a poison of some sort circulating through 
a kidney is illustrated by the black shading under a. If pieces 
of this kidney die and are absorbed while the remainder recovers 
we get ultimately the secondarily contracted kidney represented 
under b. 

If the parenchymatous nephritis is of the focal or spotty type 
as represented diagrammatically in Fig. 158, a, the changes in the 
parenchyma may again be either reversible (curable) or irreversible 
(incurable). If they are irreversible the involved patches will 
again die and be replaced b}^ connective tissue. The ultimate 
picture is shown in b of Fig. 157 and again approximates that 
previously described. Healthy kidney substance remains to 
make up the bulk of the kidney which, however, is diminished 
in amount and has connective tissue scattered through it. We 
have again a " small red kidney," in other words, again a chronic 
interstitial nephritis. But because some have assumed — falsely 
as we shall see — that the connective tissue was laid down first 



NEPHRITIS 



535 



and that the death and disappearance of parts of the kidney 
occurred later, this pathological entity has been called a primarily 
contracted kidney or a primary chronic inter stital nephritis. From 
a morphological classification point of view this kidney is about 
the same as the secondarily contracted kidney previously dis- 
cussed. 

It will make matters a little clearer if we try at once to con- 
nect up this simple classification with the clinical aspects char- 
acteristic of the described kidney states. 

If a poison capable of inducing nephritic changes circulates 
in the body of a patient, let us say the toxins of a scarlet 
fever, the toxins of a pregnancy nephritis, or bichlorid of mer- 
cury, it will, in passing through the kidney, tend on the whole 




Figure 157. Figure 158. 



to affect the entire kidney at once and more or less uniformly. 
For this reason examination in the course of a surgical opera- 
tion or postmortem reveals the swollen kidney of the so-called 
generalized parenchymatous nephritis. Since the whole kidney 
is involved, we encounter under these circumstances the greatest 
interference with function and therefore the greatest decrease 
in water output — maybe to the point of complete suppression. 
At the same time such urine as is secreted is heavily charged 
with albumin and casts. If the causes operating to produce 
the nephritis pass away, the kidney recovers and so the urinary 
output rises again and casts and albumin diminish, all, maybe, 
in the space of a few days. But if pieces of the kidney die, the 
evidences of destruction in the kidney as betrayed by casts and 
albumin may last longer, but even here if the causes operating 
to produce the nephritis are ultimately overcome, such portions 



536 



(EDEMA AND NEPHRITIS 



of the kidney as are left may recover and the patient with his 
secondarily contracted kidneys — his morphologically chronic 
interstitial nephritis — may live indefinitely. The reason for 
this resides in the fact that one-quarter of our total kidney substance 
is easily sufficient to maintain us in health and happiness, and 
if this amount has been saved the patient need show no signs 
or symptoms which will allow a diagnosis of his true condition. 
An autopsy or examination of the kidneys in the course of a 
surgical operation may offer the first occasion for recognizing 
the kidney state. 

It is hardly possible for a soluble poison to enter the kidney 
and not affect it rather uniformly. A circulating poison can 
hardly, therefore, give rise to a spotty or focal parenchymatous 
nephritis. For such we need a spotty cause. Such is offered, 
for example, by a seeding of micro-organisms into the kidney 
(infectious embolism) or by the changes consequent upon vascular 
disease. 1 We shall return to this problem later, but it may be 
emphasized here that all evidence shows the vascular disease to be 
primary and the kidney disease secondary to it. 2 Vascular 
disease attacks particularly the smallest blood vessels. (When 
it attacks the larger blood vessels it does this by attacking their 
vasavasorum.) Since the blood vessels of the kidney do not 
escape, this organ may, of course, be affected. In consequence of 
the thickening of the vascular walls and the oft-accompanying 
thrombotic changes, one piece of the kidney after another is 
deprived of its blood supply. As this happens they show the 
changes characteristic of nephritis, and since the arteries involved 
are end arteries, the kidney changes are largely irreversible, and 
piece after piece of the kidney dies and disappears while connective 
tissue takes its place. The portions of kidney involved in this 

1 Under this caption I include all the pathological processes capable of 
affecting the blood vessels, no matter what their assumed causes, be they 
frank infections as in syphilis, or "degenerations" as in atheroma, arterio- 
sclerosis, etc., popularly regarded as consequent upon attack from that 
old guard, alcohol, hard work, gout, auto-intoxication, and a meat diet. 
For further remarks on vascular disease, see pages 615, 629 and 634. 

2 See in this connection, Hauch's beautiful x-ray pictures of the blood 
vessels of healthy and diseased kidneys. In vascular disease involving 
this organ the lumina of the blood vessels become smaller and the vessels 
supplying a given area progressively less in number. When such changes 
are sufficiently advanced the involved kidney tissues die. Hauch: Fortschr. 
Rontgenstrahl. 20, 172 (1913). 



NEPHRITIS 537 

localized destruction of kidney parenchyma show all the signs char- 
acteristic of parenchymatous nephritis. Between these localized 
areas of parenchymatous nephritis the kidney tissue is healthy. 
When, now, we again remember that less than one-fourth of the 
total kidney substance is necessary for the maintenance of life, it is 
easy to see why a patient with chronic interstitial nephritis runs 
along in a fairly normal way. The destruction of the kidney 
occurs so very slowly that little albumin appears in the urine, 
and casts only in small numbers. So this patient may also die 
without ever having become conscious of his kidney state. If 
a diagnosis is made for him it is done very largely on the basis 
of findings referable to his vascular disease (palpable blood ves- 
sels, high blood pressure, cardiac hypertrophy) which as we shall 
see are not secondary to his kidney disease, but expressive of 
his vascular condition. 

We shall have occasion to return to all this later. For the 
present it is sufficient merely to emphasize the fact that the 
chronic interstitial nephritis associated with vascular disease is in 
essence also a parenchymatous nephritis — a slow-going but pro- 
gressive localized parenchymatous nephritis resulting in death and 
loss of the involved portions of the kidney and ultimately in a picture 
which is best described by calling it an atrophy of the kidney. The 
patient with chronic interstitial nephritis is, therefore, in the same 
position as an animal that has had its kidney substance progres- 
sively diminished in amount by successive operations and abla- 
tions of kidney parenchyma. The man who has gone through life 
without marked signs or symptoms of kidney disease, who dies of 
other causes than kidney disease, and shows on the autopsy table 
what, as morphologists, we call chronic interstitial nephritis, is 
simply like the animal that has suffered a great reduction in total 
kidney substance, but has not yet reached the physiological 
minimum compatible with life for that animal under the con- 
ditions under which it has to live. What is left of kidney paren- 
chyma to man or animal is still physiologically active and physi- 
ologically adequate. Such a biological contention finds its 
morphological support in the fact that the parenchyma of such 
(morphologically) chronic interstitial types of nephritis shows 
little or no change either macroscopically or microscopically 
("small red kidney ")• The presence of the connective tissue in 
the kidney is an accident; it is scar tissue, and whatever im- 



538 



OEDEMA AND NEPHRITIS 



portance we may care to attach to it morphologically, this is 
no more expressive of the physiological state of the kidney 
parenchyma that is left than the scar which repairs and serves 
to reunite the ruptured ends of a muscle is any index of the physi- 
ological efficiency of that muscle. 

With this we have disposed of the apparent differences between 
parenchymatous nephritis and what is called chronic interstitial 
nephritis. 

While infections of the kidney are not ordinarily considered 
under the nephritides, they might as well be, for the result is 
the same, of course, whether the function of the kidney is impaired 
because toxins are carried into it by the blood stream or they 
are manufactured on the spot by micro-organisms present in 
the kidney. The infections may give rise to either a generalized 
or focal type of nephritis. If tubercle bacilli, for example, or 
some of the pus formers are sown into a kidney, patches of 
nephritis result which give rise to albumin and casts in the urine 
in proportion to the amount of kidney involved. If sufficient 
healthy tissue remains between these patches the total urinary 
output need not be much changed. On the other hand, if the 
involved patches increase in size or become so numerous as to 
take up the major portion of each kidney, then albumin and casts 
must increase and urinary secretion diminish even to the point 
of complete suppression perhaps. If destruction of kidney tissue 
results with replacement by scar tissue these infectious cases 
also yield secondarily contracted kidneys (chronic interstitial 
nephritis) . 

Let us complete this discussion by referring once more to 
Figs. 157 and 158. Under b of Fig. 157 is represented the atrophic 
remains of a healthy kidney which is called, morphologically, 
chronic interstitial nephritis. Such a kidney is, of course, as sub- 
ject to attack by any of the causes which may underlie a general- 
ized parenchymatous nephritis as is a normal kidney. When 
this occurs the normal or " increased " urinary output so often 
observed in the morphologically chronic interstitial nephritides 
gives way to a diminished one with many casts and much albumin. 
This is frequently the terminal picture in the chronic interstitial 
types of nephritis found associated with vascular disease and its 
accompanying cardiac hypertrophy and high blood pressure. 
The chronic interstitial nephritis is produced as already described. 



NEPHRITIS 



539 



But while the patient is living on his remnants of kidney, his 
heart muscle begins to fail or the sclerosis of the main arteries 
leading into the kidney reaches a fatal limit, and subject to the 
inadequate blood supply resulting from such the remaining 
kidney cells die — the " small red kidney " (Fig. 157, b) passes 
over into the " small gray " one (Fig. 158, 6). 

We shall find much evidence to support these simple views as 
we proceed. What will strike my readers at this time as the most 
obvious shortcoming in my insistence that the chronic interstitial 
types are also but parenchymatous nephritides, is my ignoring 
of the fact that with the frankly parenchymatous types we are 
likely to find associated a generalized oedema, while with some of 
the recognized types of chronic interstitial nephritis there goes 
no oedema, but an increased blood pressure and cardiac hyper- 
trophy. I am ignoring these things only temporarily, however. 
But even here let me point out what will be proved later, that 
these signs, while likely to be associated with these types of 
nephritis, are not secondary to the kidney disease as generally 
taught, but due to entirely different causes. 1 

Let us now discuss the morphological changes observed in 
the nephritic kidney seriatim. The pathologist accepts the fol- 
lowing as characteristic of the parenchymatous lesions whether 
they involve patches or the whole of a kidney. For their recog- 
nition no elaborate histological technique is at all necessary. 

1. An increase in the size of the involved portions of the kidney, 
traceable on the examination of fresh, unfixed and unstained cells, 
back to an increase in the size of the individual cells and tissues 
composing the kidney. 

2. A loss of the normal color of parts or all of the kidney which 
assume a less glistening, drier and more opaque (boiled) look. 
On microscopic examination this change is found to be associated 
with the appearance of granular substances in the cells of the 
affected portions of the kidney. This change in color, taken in 
conjunction with the increase in the size of the kidney, con- 
stitutes the " cloudy swelling " of the pathologists. 

3. The appearance of blood corpuscles extra vascularly. They 
may be found in the tissues of the kidney itself, or in the spaces 
about the glomerular tufts and in the uriniferous tubules. 

4. Evidences of a falling apart of the kidney as a whole and 

1 See page 614. 



540 



(EDEMA AND NEPHRITIS 



of a disintegration of the individual cells of the kidney. Under 
this heading are grouped not only the gross destructive lesions 
observed in the kidney, such as the rupture of capillary tufts, 
but the separation of individual and groups of cells from their 
attachments in the glomeruli, Bowman's capsule and the urin- 
iferous tubules (formation of casts). 

This catalog of morphological changes holds both for the 
acute parenchymatous nephritides and for the chronic forms. 
The chronic show all the changes of the acute with certain others 
added to them, notably a " fatty degeneration," and the develop- 
ment of a certain amount of scar tissue. As the last two take 
us into fields not immediately connected with our problem of 
nephritis, we shall not discuss them in detail. 1 

3. The Changes in the Size and in the Color of the Kidney in 
Nephritis (Cloudy Swelling) 2 

§ 1 

While we shall later find ourselves compelled to discuss 
these two changes in the kidney separately, we will first take 
them up together because it is in this form, under the caption 
of cloudy swelling, that they have been chiefly discussed by the 
pathologists. 

As is familiarly known, we are indebted to Rudolph Virchow 
not alone for a first clean-cut description of this cloudy swelling 
as it occurs in the kidney (and other parenchymatous organs), 
but for a first attempt to analyze its nature. Virchow held 
cloudy swelling to be " a kind of acute hypertrophy with tendency 
to degeneration/ ' a phrase which has found its way into even 
our most modern text-books of pathology. But while such a 
phrase still serves many as a satisfactory characterization of the 
condition from a biological standpoint, it means nothing, of course, 
from the standpoint of its physico-chemical analysis. Toward' 
the physico-chemical analysis of cloudy swelling Virchow con- 
tributed the important suggestion that the cause of the granule 
formation in the cells is due to a change in their albuminous 

1 For a detailed study of fatty degeneration which has appeared since 
this paragraph was written see Martin H. Fischer and Marian O. Hooker: 
Fats and Fatty Degeneration, New York (1917); or Science, 43, 468 (1916); 
Kolloid-Zeitschr., 18, 129 (1916); ibid., 18, 242 (1916). 

2 Martin H, Fischer: Kolloid-Zeitschr., 8, 159 (1911). 



NEPHRITIS 



541 



constitution. He based this conclusion upon the fact that the 
granules are soluble in acids and alkalies, and not in ether, thereby- 
distinguishing them from fat deposits in the cells (fatty degenera- 
tion) which at times mimic in general appearance cells affected 
by cloudy swelling. For the increase in the size of the cells 
Vikchow gave only the biological explanation of an " increased 
irritation " of the affected cells, caused, for example, by the 
products of an infectious disease, in consequence of which they 
were made to take up " excessive amounts of nutrient material. " 

That cloudy swelling represents a change in the albuminous' 
constitution of the cell seems never to have been questioned. 
Eduakd Rindfleisch 1 accepted this belief and, moreover, 
expressed himself of the opinion that cloudy swelling was " pass- 
ive " in its nature and due to " a kind of corrosive action in con- 
sequence of which the albuminous matters, held in solution by 
the protoplasm, undergo coagulation and become visible as 
minute granules." In 1882 Julius Cohnheim 2 subjected Vm- 
chow's teachings to a rigorous critique. That the process of 
cloudy swelling involved the albuminous constituents of the cell 
he did not question, but he perpetuated a conclusion (erroneous 
as we shall see) of Virchow, when he wrote: " Of course we must 
deal here with a protein that is different from that which is nor- 
mally present in the cell protoplasm ... as we could not other- 
wise account for the optical difference." But Cohnheim, too, 
expressed the possibility of cloudy swelling representing " a 
spontaneous precipitation in solid form, or the coagulation of a 
previously fluid protein." What underlies such a change in the 
albuminous constitution of the cell, he did not attempt to say, 
but he showed conclusively that the causes proposed by earlier 
writers were questionable if not entirely inadequate. Thus 
he showed that the fever accompanying the various infections 
liable to be accompanied by a cloudy swelling could not by itself 
be the cause of the change, by calling attention to the well-known 
fact that cloudy swelling may be absent in cases that have run 
a high fever, or present in conditions not associated with an 
abnormal rise in temperature. 

1 Eduard Rindfleisch: Pathological Histology, translated by Baxter, 
30, London (1872). 

2 Julius Cohnheim: Allgemeine Pathologie, 2d Ed., 1, 662; 2, 570, 
Berlin (1882). 



542 



(EDEMA AND NEPHRITIS 



In such a half-hypothetical state did the subject of cloudy 
swelling remain until 1901, for in spite of various discussions 
of the subject, no clear-cut advance was made either toward 
defining more precisely what cloudy swelling is, nor yet in dis- 
covering a something common to all conditions associated with 
cloudy swelling, which might justly be regarded as its funda- 
mental "cause." At this time H. J. Hamburger 1 reported a 
series of observations on isolated liver, kidney and spleen cells 
which served to establish more firmly what can justly be regarded 
as little more than lucky speculation on the part of the earlier 
writers. Hamburger applied to these cells observations pre- 
viously made on red and white blood corpuscles. In a study of 
the latter he had found that various acids, including carbonic 
acid, bring about an exchange of substances, including water, 
between the red and white blood corpuscles and the serum in 
which they are contained. Under the influence of acids all these 
cells take up water from their surroundings. He paralleled this 
with the findings of previous observers that, in fevers of the most 
varied origins, acids are produced and the " alkalinity " of the 
blood is reduced, and so concluded that in this acid production 
resided the cause for the enlargement of the cells in cloudy swelling. 
He debates why acids bring about the enlargement and con- 
cludes that changes leading in the aggregate to an increase 
in the osmotic pressure of the cell contents are mainly respon- 
sible. Hamburger then points out that the white opaque 
appearance of isolated kidney, liver and spleen cells exposed to 
dilute acids is identical with that of cells affected with cloudy 
swelling and discovered postmortem. Cells treated with an 
acid are studded with granules, as are the cells showing a cloudy 
swelling that are found postmortem, and to prove that the gran- 
ules are similar in character in both, and represent protein pre- 
cipitates, he calls attention to the fact that the granules which 
he had made appear through a weak acid dissolved again as the 
acid concentration was increased. Hamburger found an analog 
of the production of the granules in the isolated parenchyma 
cells in the precipitation of protein from a diluted blood serum 
when an acid is added to this. 

1 H. J. Hambuegee: Osmotischer Druck und Ionenlehre, 3, 49, Wies- 
baden (1904), where references to his earlier articles may be found. See 
also Kael Laxdsteixee: Ziegler's Beitrage, 33, 237 (1903). 



NEPHRITIS 



543 



The first great value of Hamburger's studies resides in the fact 
that he has detailed experiments which show that all the neces- 
sary elements for cloudy swelling reside in the parenchymatous 
cells themselves, and that he has pointed out that what is added 
through an infectious disease (or, as we might say, in order to 
make our contention more pointed, any condition which is capable 
of inducing a nephritis) may be nothing more than a little acid. 
This simple reasoning of Hamburger does away with the bio- 
logical terminology that has so long been applied to the subject 
of cloudy swelling, and renders possible an attack upon the 
problem in the light of the simpler concepts of physics and 
chemistry. 

Since Hamburger's work I know of no contributions to the 
subject of cloudy swelling which have either questioned the 
correctness of his view, that the increased absorption of water 
by the cell affected with cloudy swelling represents an osmotic 
phenomenon, nor any which have adduced further evidence in 
support of the protein precipitation idea of the granule forma- 
tion in this condition. As the subject is intimately connected 
with our problem of the morphological changes occurring in 
nephritis, I felt that it could to advantage be restudied, espe- 
cially since the acquisitions of colloid chemistry — the chem- 
istry of the very substances of which the kidney is composed 
— have furnished us with data and theoretical deductions that 
are of immediate applicability in the analysis of this problem. 
By utilizing these we shall find ourselves in a position to give a 
simpler physico-chemical explanation for the increased water 
absorption by the tissues in cloudy swelling than is contained 
in the unsatisfactory osmotic explanation of this part of the 
phenomenon, and at the same time we shall learn how the clouding 
of the parenchymatous organs follows the same laws as the pre- 
cipitation of such a simple colloid as casein. In this way we shall 
find a ready explanation of the first two of the morphological 
changes in the kidney catalogued above and characteristic of 
nephritis, namely, the increase in the size of the parenchymatous 
elements and their change in color. At the same time we shall 
find that both arise from the same cause, namely, the abnormal 
production and accumulation of acid in the kidney, which we have 
previously tried to show to lie at the base of all the nephritldes. 



544 



(EDEMA AND NEPHRITIS 



§ 2 

We shall first describe a series of observations on the arti- 
ficial production in excised kidneys of the changes characteristic 
of nephritis (production of .cloudy swelling) which will prove 
themselves of service in the further analysis of our problem. 
The methods employed in these experiments were the same 
throughout. The kidneys of healthy, freshly killed rabbits 
and guinea pigs were used, which after being sliced were dis- 
tributed into bowls each containing 100 cc. of the necessary 
solutions. As it is impossible to give absolute values to the 
various grades of grayness and opacity observed in the different 
solutions, one can, in the description of the findings, only com- 
pare the appearance of a tissue in one solution with that of a 
similar piece in a different solution at the same time. The gen- 
eral conclusions from a long series of experiments may be sum- 
marized as follows: 

(a) When slices of fresh kidney are dropped into distilled 
water they slowly swell and at the same time become gray. A 
tone of gray that is readily distinguishable from the color of the 
normal organ appears over the cut surface some three or four 
hours after being dropped into the water. This gradually 
increases in intensity until, twenty-four hours after the begin- 
ning of the experiment, the tissues look decidedly gray. For a 
day or two longer this may continue to increase in intensity, 
but the change from the first twenty-four hours is not very 
marked. As the tissue becomes gray it shows an acid reaction 
to litmus, and this acid production in even a small piece of tissue 
may be sufficiently great to impart an acid reaction to the sur- 
rounding fluid. 

(6) The pieces of tissue swell much more rapidly if they are 
placed in any dilute acid instead of in distilled water. This is 
shown in Fig. 159. A has simply been protected against evapo- 
ration. B has lain for an hour and a half in n/333 hydrochloric 
acid. The two pictures represent opposite faces of the same 
cut through the kidney. The tissues also become gray sooner 
in an acid solution than in distilled water. In n/200 solutions 
of lactic, formic, acetic, tartaric, hydrochloric, sulphuric, or 
nitric acids a decided cloudiness is visible in ten minutes after 
immersion. This cloudiness becomes gradually more marked. 



NEPHRITIS 



545 



After three hours, when the control in distilled water is just 
showing a grayness, the slices of tissue in the dilute acids are 
grayer than the controls appear the following day. The vari- 
ous acids show some difference in the intensity of the cloudi- 
ness that they produce, but this is so much a function of their 
concentration and the time, that a table of their relative effective- 
ness cannot be given to advantage. After another two hours the 
tissues in all the acid solutions are intensely gray. The control 
in pure water is about as gray as the tissues placed in the dilute 
acids were after ten minutes of immersion. On the following 
day an ultimate degree of grayness (a typical "boiled " appear- 
ance) is shown by all the organs in the dilute acids. 




A B 

Figure 159. 



Speaking generally, it may be said that when the effects of 
different concentrations of the same acid are compared, the 
cloudiness develops the more rapidly the greater the concentra- 
tion of the acid. So far as intensity is concerned, there is, how- 
ever, little difference. In the end every acid gives the tissues 
a boiled appearance. With different concentrations of nitric 
acid I found the boiled appearance after a ten-minute immersion 
in n/10 normal acid. In n/20 acid the same appearance was 
attained in an hour; in n/40, n/100 and n/500 in two to three 
hours. 

What has been said of nitric acid holds true in general for 
all acids, though there are more or less specific differences 
with the different acids both so far as rapidity of development 
and intensity of the cloudy swelling is concerned. Acetic acid 



546 



(EDEMA AND NEPHRITIS 



is particularly interesting. With increasing concentrations of 
the acid there is first an increase in the rate and (in units of time) 
in the intensity of the cloudiness produced. If we observe 
closely, this is seen to be followed with increasing concentra- 
tions of acid (above n 10 acetic acid) by a stage in which the 
cloudiness is less than in lower concentrations. To see these 
successive changes one must observe especially the superficial 
portions of the tissues. A second clouding can now be obtained 
by changing to one of the " strong " acids (nitric, sulphuric, 
or hydrochloric) of the same or of a higher normality than that 
of the acetic acid which has brought about the disappearance 
of the first clouding. This change from cloudiness to clear- 
ness and back again to cloudiness, with progressive increase in 
the concentration of an acid, can be followed particularly well 
under the microscope (see (g) below). But even in the sections 
of tissue kept in the " stronger " acids can two such regions 
of cloudiness separated by one of clearness be discerned. I 
found, for example, that the marked cloudiness of slices of kidney, 
which had been kept for 1J hours in concentrations of nitric 
acid up to n 200, disappeared when the surface of the organ 
was touched with the ordinary weak acetic acid of our lab- 
oratory reagents, to reappear when dilute nitric acid was sub- 
stituted for it. 

The cloudiness of the tissues obtained in any of the acids 
listed above, if developed in not too high concentrations (below 
n/200), can also be made to disappear if the tissues are placed 
in equinormal alkali solutions, or in alkali solutions of a higher 
concentration. 

(c) Through the addition of various salts the develop- 
ment of a cloudiness in any acid solution can be either retarded 
or hastened. So far as the absorption of water is concerned, 
all the salts have but one effect — they decrease the amount of 
the swelling in the acid solution. When to n 200 hydrochloric 
acid enough of various potassium salts is added to make their 
final concentration m/20, the following is noted. After ten 
minutes' immersion it is plainly evident that some of the salts 
are accelerating the effect of the acid in producing the devel- 
opment of the cloudiness, while others are inhibiting it. In 
an hour the differences are very marked. The sulphocyanate, 
iodid, bromid, and nitrate all increase the cloudiness, the first 



NEPHRITIS 



547 



named being the most powerful in this respect. Then comes 
the pure acid. Following this comes the chlorid, the acetate, 
the tartrate, and the citrate. After three to six hours of im- 
mersion the differences are still more striking. In the solutions 
containing the first-mentioned salts the tissues are " boiled " 
in appearance. In the pure acid the grayness is well marked. 
The tissues in the solutions containing the chlorid and the 
acetate lag somewhat behind the pure acid. In the tartrate 
a faint film is only just visible over the surfaces of the organs. 
The sections in the solutions containing the citrate look per- 
fectly normal. In fact, in the two last-named solutions the 
organs retain an almost normal appearance for two to three 
days. 

Similar results are obtainable by using sodium or ammo- 
nium salts in place of the potassium salts, or lactic, formic, 
or nitric acid in place of the hydrochloric, except that in the 
latter case the absolute rate at which any degree of cloudiness 
is obtained is not quite the same as in hydrochloric acid. 

(d) Various salts accelerate or retard the development 
of a cloudiness in sections of kidney placed in their pure 
solutions, in the same way as they accelerate or retard the 
development of a cloudiness if an acid is added at the same 
time, only the rate of development and the absolute intensity 
of the cloudiness attained is less in the pure salt solutions than in 
mixtures of these with any acid. In all salt solutions the kidney 
slices swell less than in pure water. These findings are to be 
interpreted by noting that the excised tissues become acid, so that 
the tissues placed in the pure salt solutions are really in the same 
state as the tissues described in the preceding paragraph — 
the tissues are really in an acid solution plus certain salts — 
only the concentration of acid is lower in this case than in the 
previously described experiments. 

(e) Alkalies do not produce a cloudiness of kidney parenchyma 
in any concentration. Sodium, potassium, ammonium, and 
calcium hydroxids were employed in concentrations up to n/33. 
The superficial layers of the tissue slices " dissolve " in the 
hydroxids, covering the tissues with a clear, gluey mass. After 
two or three days the tissues lose their bright normal color, 
but the grayness assumed is only slight. The slices of kidney 
swell just as they do in acid solutions. 



548 



(EDEMA AND NEPHRITIS 



(/) The addition of any salt to the solution of an alkali does 
not lead to any cloudiness of the tissues, though it markedly 
reduces the tendency of the superficial layers of the tissues to go 
into " solution," and the swelling of the tissue fragments as a 
whole. I have tried without effect the chlorids, bromids, iodids, 
nitrates, sulphates, sulphocyanates, acetates, tartrates, and 
citrates of sodium, potassium, and ammonium in conjunction 
with the hydroxids of sodium, potassium, and ammonium. I 
have also tried a few strontium and barium salts with these 
hydroxids and calcium hydroxid, employing all in such low con- 
centrations as to prevent the formation of precipitates, but I 
got no cloudiness of the immersed tissues. 

(g) The macroscopic changes observed in the kidney when 
immersed in water, various acids or alkalies, in salt solutions, 
or these in combination, show a series of interesting parallels 
microscopically. 

A perfectly fresh scraping from the kidney shows the cells 
to possess a fairly clear protoplasm in which lie but few granules. 
Even after the kidney cells have been kept for twenty-four hours 
(simply in their own moisture, and protected against evapora- 
tion by being covered) they show no change from this appearance. 
But as soon as water touches the cells, especially if the organ has 
been kept for twenty-four hours, or if they are placed in any 
very dilute acid, a grayish film is seen to develop macroscopically, 
and microscopically the cells are now found thickly studded with 
granules. This is the typical histological picture of the cloudy 
swelling described in our text-books of pathology. If now, 
while such cells are being observed, a little caustic soda is 
allowed to run under the cover slip, the cells as a whole are seen 
to swell, the granules to become fainter, then fewer, and finally 
to disappear entirely, and if enough alkali is added the whole 
goes into homogeneous " solution." 

The granules can also be made to disappear by the addi- 
tion of more acid; they form, for example, in very dilute acid, 
and disappear again if the concentration of this same acid is 
raised. Most interesting is the fact that this granular appear- 
ance can be made to come a second time by still further increas- 
ing the concentration of the acid. Acetic acid will not do this, 
but nitric acid will do it promptly. If strong nitric acid is used 
this second appearance of the granules is only a temporary affair, 



NEPHRITIS 



549 



for they again disappear as the whole tissue goes into "solu- 
tion." With the second appearance of the granules the cells 
undergo a marked shrinkage from the more swollen state attained 
previously, but this shrinkage, like the second appearance of 
the granules, is also only temporary, and the cell undergoes 
a final enormous swelling before being " dissolved.' ' 

§3 

How now are we to interpret these various findings, and 
what light do they bring us regarding the cause and the essen- 
tial nature of those changes of like character, which we observe 
in the kidney in nephritis and which lead to the increase in its 
size and to the change in its color. Our first attention must 
be dedicated to the increase in the size of the cells. 

H. J. Hamburger recognized clearly that the fundamental 
cause for the increase in the size of the cells affected with 
cloudy swelling lies in the production of acid in them. As we 
have already learned, evidences of an abnormal production 
and accumulation of acid in the kidney occurs in every case of 
nephritis, and so we may make this circumstance, which we have 
already made responsible for the albuminuria, responsible for 
this increase in the size of the kidney also. But how does an 
abnormal acid content manage to bring about the increased 
water absorption which leads to the increase in the size of 
the cells (and so of the kidney as a whole) in nephritis? Ham- 
burger answered this question by attributing an indirect effect 
to the acid, whereby this was assumed to increase the osmotic 
concentration within the cells. The enlargement of the cells in 
" cloudy swelling " represents an cedema of the affected cells, and 
this is most easily accounted for on the basis of the colloid 
constitution of living matter. The serious objections that 
can be lodged against the widely accepted belief that cells 
represent osmotic systems cannot be raised against the view 
that the lyophilic colloids of the tissues and their state deter- 
mine the quantity of water absorbed by a cell. As previously 
emphasized, the amount of water that such colloids (as rep- 
resented by gelatin, fibrin, and serum albumin, for example) 
. will absorb is enormously increased if any acid is present. This 
fact receives incidental illustration in Fig. 148. On this basis, 



550 



OEDEMA AND NEPHRITIS 



it is easy to parallel the absorption of water, and so the enlarge- 
ment of the cells of the kidney when affected by nephritis, with 
the increased amount of water absorbed, say by a gelatin cube or some 
fibrin particles, when instead of being placed in water they are 
placed in a dilute acid of some kind. In the case of gelatin and 
fibrin, and similarly in the case of the experiments on excised 
kidneys, the source of the water for the increased swelling is to 
be found in the solutions surrounding these colloid structures; 
in the case of the nephritic kidney, in the blood and lymph 
streams passing through the organ. 

There is, within certain limits, an increase in the amount 
of the swelling of such protein colloids as gelatin or fibrin with 
every increase in the concentration of the acid surrounding them. 
On this basis we can understand the increase in the swelling 
of the kidney cells with every increase in concentration of the 
acid up to a certain point. When a certain optimal concentra- 
tion of the acid is exceeded, the colloid swells less than in weaker 
solutions (see Fig. 148). This furnishes a ready interpretation 
of the finding detailed above, that on substituting nitric acid 
for a weaker solution of acetic acid, kidney and liver cells are 
seen to shrink. Incidentally, it is worth while emphasizing 
that in the great rapidity with which such cells will give off 
and take up water, in changing from a medium of one concen- 
tration to another having a lower or a higher one, lies a powerful 
argument against the osmotic pressure idea of water absorption 
in cells. I have seen these cells pass from the swollen state, 
in a weak acetic acid solution, to the greatly shrunken state 
induced by nitric acid, and through a second swollen state 
into " solution " in less th^n two seconds. Equalizations of 
osmotic differences either through a movement of solvent, or 
of dissolved substance, do not occur with such velocity. 

We may now turn to a consideration of the changes in the 
color of the kidney in nephritis, and see how these become inter- 
pretable on the basis of the fact that in this condition an abnor- 
mal amount of acid is present in the kidney. 

The statements made above regarding the means by which 
a cloudiness can be produced in the parenchymatous cells of 
the kidney, or regarding its rate of development, or the means 
by which the intensity of such a cloudiness may be increased 
or decreased, have all of them parallels in the ways and means 



NEPHRITIS 



551 



by which protein may be precipitated from one of its " solu- 
tions," or such a precipitation be hastened or retarded. The 
development of a cloudiness in the kidney cells follows most closely 
the solution and precipitation of such a colloid as casein. 1 

Casein 2 is insoluble in water. It is soluble in dilute hydroxids, 
in which state it is electro-negative. It is in this state that we 
find the body proteins normally, as Wolfgang Pauli 3 has 
shown. In the left-hand tube of Fig. 160 is shown the perfectly 
clear casein solution made by saturating an alkali (NaOH) with 




Figure 160. 



casein. When a dilute acid is added to such an electro-negative 
protein, let us say to the solution of casein in any hydroxid, a 
precipitate of the casein is thrown down, as shown in the second 
tube. A similar precipitation of an electro-negative colloid 

1 This term is used in Hammarsten's sense and corresponds therefore 
with the caseinogen of Halliburton. 

2 For a discussion of the general properties of casein see O. Hammarsten: 
Physiological Chemistry, translated by Mandel, New York (1914); E. 
Laqueur and O. Sackur: Hofmeister's Beitrage, 3, 193 (1903); W. A. 
Osborne: Jour. Physiol., 27, 398 (1901); T. B. Robertson: Jour. Biol. 
Chem., 2, 317 (1907); L. L. van Slyke and E. B. Hart: Am. Chem. 
Jour., 33, 461 (1905). 

3 Wolfgang Pauli: Naturwissensch. Rundschau, 21, 3 (1906). 



552 (EDEMA AND NEPHRITIS 

occurs when our sections of kidney are immersed in any dilute 
acid. The development of a cloudiness in tissues immersed in 
water is also to be regarded as a precipitation through a dilute 
acid, only in this case the tissues themselves produce the acid. 
Similar conditions hold in nephritis, when, in consequence of 
the abnormal acid content of the kidney, some of the protein 
constituents of the cells composing this organ are precipitated. 
As we have already found this same acid to be responsible for an 
increased swelling of the tissue colloids, it is easy to see how 
from the two there results, when water is available, the picture 
we designate " cloudy swelling." 

But our analogy goes further than this. If we continue 
to add acid to the reaction mixture in which our casein began 
to be precipitated, the precipitate becomes heavier (as in the 
third and fourth tubes of Fig. 160), but soon, with still further 
addition of acid, the casein begins to go back into solution. This 
is evident in tubes five, six, and seven, the last of which is again 
entirely clear (the white spot at the bottom of the tube in the 
photograph being a highlight). This is what we observe in the 
kidney cells when we note the cloudiness produced in a weak 
solution of any acid, or that found in the nephritic kidney on 
autopsy, to disappear on applying a stronger solution of the 
acid (say acetic acid) to the kidney. This macroscopic change 
has its parallel in the microscopic disappearance of existing 
granules in a cell, the seat of a cloudy swelling (found either 
postmortem or induced artificially), when acetic acid is run 
under the coverslip. But the casein thus redissolved in such 
an acid as acetic acid can be precipitated a second time if 
strong nitric (or hydrochloric or sulphuric) acid is allowed to 
flow into the test-tube as shown in the tube on the extreme 
right of Fig. 160. If the protein is not present in excessive 
amounts, this second precipitate also disappears — we say it goes 
into solution in the excess of the nitric acid. It is not difficult 
to see that this is entirely analogous to the reappearance of 
granules in the kidney cells, with subsequent total solution of 
the affected cells, on the addition of nitric acid for example, to 
cells in which a previous set of granules has been made to dis- 
appear by the addition of acetic acid. 

Equinormal solutions of different acids are not equally 
effective in producing a precipitation of casein; neither are they 



NEPHRITIS 



553 



equally effective in producing the cloudiness of cloudy swelling. 
In low concentrations certain salts favor the precipitation of 
casein by dilute acids while others hinder this. The sulpho- 
cyanates and iodides quickly precipitate casein from an acid 
solution in heavy curds. Equimolar solutions of the bromids, 
nitrates, and chlorids produce only an opalescence, while in 
citrates the casein remains in solution. When arranged accord- 
ing to the intensity with which these acid radicals favor the 
development of a cloudiness in the kidney the order is the same. 
Various basic radicals, in the dilute solutions in which they have 
to be used to prevent their precipitation as hydroxids, do not 
influence the precipitation of casein. Neither do they affect 
the development of cell cloudiness. 

Kidney cells also follow the behavior of casein toward alkalies. 
All the alkalies make casein go into solution and, similarly, the 
alkalies do not produce any clouding in kidney cells. 1 Casein 
is not precipitated in alkaline solution by the addition of any of 
the ordinary salts. Neither is a cloudiness produced when 
any salts are added to slices of liver or kidney immersed in a 
dilute alkali. 

Point for point the analogy between the precipitation of 
casein and the artificial development of a cloudiness in kidney 
cells seems therefore to be complete, and since there exists no 
discoverable difference between the changes thus artificially 
induced in excised kidneys and those which nature produces 
for us in this same organ in nephritis, nor yet in the conditions 
leading to these changes in either case, we would seem to be 
justified in considering all these changes as in essence the same, 
and as caused fundamentally by the same circumstances. 

As this process of cloudy swelling represents a series of 
changes in the state of the cell colloids, it is clear that the 
employment of any methods in its study — such as fixing agents 
and various stains — which in themselves are capable of pro- 
ducing changes in the state of cell colloids, should be excluded. 
Nevertheless, to meet the possible objection that what has been 
described in these pages as cloudy swelling might really not be 
identical with this change as observed on the autopsy table, our 

1 The slight grayness developed by slices of kidney, kept for several days 
in a dilute alkali, has its parallel in the turbidness which we find developed in 
alkaline solutions of casein, when these are kept for longer periods of time. 



554 



(EDEMA AND NEPHRITIS 



pathologist, Paul G. Woolley, generously offered to examine 
by approved histological methods the tissues in which I had 
produced cloudy swelling artificially. He reports that the pictures 
obtained are identical with the most extreme grades of cloudy 
swelling that are encountered pathologically. 

In concluding these paragraphs we have to answer the 
final question of the relation of the swelling of the kidney cells 
to the clouding in them. On the basis of the fundamental work 
of Wolfgang Pauli 1 and his coworkers, Hans Handovsky 
and Karl Schorr, this is easily done. These investigators have 
emphasized that the swelling and solution of a protein colloid are 
the antitheses of the loss of water by and the precipitation (dehy- 
dration) of the same colloid, — that the two processes are therefore 
mutually exclusive. It follows from this that the swelling of 
the cells in a parenchymatous nephritis, and the development 
of a cloudiness in them, cannot possibly involve but one colloid 
— in other words, at least two must be involved. The con- 
ditions which permit the one of these to imbibe water and so 
to lead to an increase in the size of the cell are of such a char- 
acter as to lead to the precipitation of another, and so to the 
cloudiness. Wolfgang Pauli kindly advised me to test out 
this idea in a model made by pouring a solution of casein 
(prepared by saturating sodium hydroxid with casein) into a 
concentrated, carefully washed gelatin (20 per cent) and allowing 
the whole to stiffen. When plates are cut from such a mixture 
they swell (absorption of water by the gelatin) and become 
cloudy (precipitation of casein) under the same conditions 
(presence of acids and various salts) as were found above to 
lead to a " cloudy swelling " in slices of kidney. 

1 Wo. Pauli: Kolloid-Zeitschr., 7, 241 (1910); Pauli and H. Handovsky: 
Biochem. Zeitschr., 18, 240 (1909), 24, 239 (1910); H. Handovsky: Kolloid- 
Zeitschr., 7, 183, 167 (1910); Fortschritte in der Kolloidchemie der Eiweiss- 
korper, Dresden (1911); Karl Schorr: Cited by Pauli and Handovsky. 



NEPHRITIS 



555 



4. The Bleeding into and from the Kidney in Nephritis 
(Hemorrhage by Diapedesis) 

The blood that appears in the urine in some cases of nephritis 
is of purely traumatic origin, in other words, capillaries or larger 
blood vessels are ruptured and the blood escapes. In large 
part, however, pathologists hold that blood corpuscles get from 
the, capillaries into the urine by a process of diapedesis. Through 
diapedesis are also explained many of the hemorrhages into the 
kidney substance itself. As such bleeding does not occur from 
the normal kidney we become interested in its mechanism, and 
it becomes a part of our problem to discover why in nephritis 
such a process which occurs also in other pathological states 
should be especially prone to appear. 

We still lack a satisfactory explanation of the mechanism 
of diapedesis. Our present teachings continue to partake of 
the views of von Recklinghausen and Julius Arnold, who 
held that holes (so-called stomata) exist in the capillaries, and 
that through these the red blood corpuscles escape in conditions 
associated with a bleeding by diapedesis. But such a concep- 
tion, as Julius Cohnheim pointed out years ago, is grossly 
incorrect, for what escapes from the blood is not the whole blood, 
but only the red blood corpuscles, and it is inconceivable how 
holes which would permit the passage of the cellular elements 
of the blood through them should hold back the liquid portion 
of the blood. Cohnheim believed diapedesis to be dependent 
upon changes in the blood vessel walls whereby these became 
abnormally permeable, after which he held the blood pressure 
to be able to force the red blood corpuscles through them. How 
such an abnormal permeability was brought about he declared 
himself unable to explain. 

Hemorrhage by diapedesis, while discussed by us because 
present in some forms of nephritis, is really, of course, a widely 
distributed pathological phenomenon. As is familiarly known, 
it occurs in any well-marked passive congestion, produced, 
for example, by ligation of the veins of any of the parenchymatous 
organs, of the mesenteric veins, or of those coming from the 
leg or the ear of a rabbit or dog. But it occurs also after ligation 
of the arterial blocd supply to a part, 1 and I have observed it in 

1 See page 269. 



556 



(EDEMA AND NEPHRITIS 



the entire absence of any circulation in the legs of frogs so ligated 
as to close both arteries and veins, and kept in a little water. 
Hemorrhage by diapedesis occurs also in conjunction with the 
acuter forms of inflammation no matter how induced. 

These remarks make it clear that blood pressure, which 
might at first sight be thought to be of some importance in 
squeezing the red blood corpuscles out of the blood vessels into 
the surrounding tissues, cannot be of great importance in this 
regard, for diapedesis occurs in conditions associated with a 
decrease in the blood pressure, or, as just pointed out, even in 
its entire absence. What is present in all the conditions noted 
is such a disturbance in the circulation as to lead to a state of 
lack of oxygen in the tissues, and, we have to repeat, an abnormal 
production and accumulation of acids in the affected regions. 
And this is what we have in the kidney in nephritis. But how 
does this now lead to the diapedesis? The answer is not hard 
to find. 

We have already called attention to the well-known fact 
that the cells of the living organism represent in the main a mix- 
ture of several so-called lyophilic colloids. Under normal cir- 
cumstances in the body these are in a swollen state that is sim- 
ilar to that assumed by fibrin or gelatin when placed in water. 
If a little acid is introduced into such a colloid the absorption of 
water by it is enormously increased, and as we have already 
pointed out, this is what happens when acid is introduced 
into the kidney (or into the tissues of the other parenchymatous 
organs, the intestine, the leg or the ear), in other words, an 
" cedema " develops. But this increased absorption of water 
makes the tissue softer (or, to put it more technically, its internal 
friction is decreased and its surface tension is changed) and now 
the red blood corpuscle which lies in contact with its surface is 
no longer held out by the surface layer of the tissue colloids 
(the blood vessel wall), but penetrates this — is really " swallowed " 
by the tissue. The increased fluidity of the kidney tissues, 
after these have been treated with a little acid in the presence 
of water, is readily observable under the microscope. The cells 
can be pushed about and molded on slight pressure in a most 
striking way. 

What makes the red blood corpuscle move through the tissues 
are inequalities in the stresses present in the tissue colloids. By 



NEPHRITIS 



557 



a process, the reverse of that described, the tissue which has 
once swallowed a red blood corpuscle may again get rid of it, 
though in practice such a result is hardly to be expected, for after 
a softened tissue that has swallowed some red blood corpuscles 
has a more normal circulation restored to it, it is likely to lose its 
excess of acid, and therefore its water, so rapidly that the red 
blood corpuscles remain behind entangled in the tissues. As a 
matter of fact, we know that red blood corpuscles which have 
escaped unto the tissues are usually absorbed indirectly after 
they have disintegrated. 

What we have said here regarding the red blood corpuscles 
holds also, of course, for the white blood corpuscles, only these 
possess in addition independent powers of movement which are 
lacking to the red blood corpuscles. 1 More strictly in the class 
with the red blood corpuscles belong the bacteria which we know 
may reach the kidney from any part of the body and pass through 
the kidney substance into the urine. 

Briefly formulated, the problem of how in nephritis the red blood 
corpuscles pass into the tissues of the kidney or through these out 
into the urine, or the problem of how white blood corpuscles or bac- 
teria do this comes to be the problem of how one colloid body may 
pass through another, and of the laws that govern such a passage. 
No holes are necessary in order that one colloid may pass through 
another, and such a passage is accomplished without one colloid 
losing its identity in the other or leaving behind it any evidence 
of its passage. 

The matter can be prettily illustrated by letting a mercury 
drop or solid metals (iron fragments or shot, or these covered 
with colloid material as agar-agar or collodion), under the influ- 
ence of gravity, move in all directions through a solidified gelatin. 
The mercury is particularly suitable, for, while not a colloid, 
it has the " liquid " character possessed by the red and white 
corpuscles. In the body the migration of the blood corpuscles 
(or metal fragments, etc.) does not, of course, occur under the 

1 In the discussion of the migration of white blood corpuscles in inflamma- 
tion (chemotaxis) most emphasis is always laid upon the changes that the 
white blood corpuscles themselves are believed to suffer (for example, 
changes in surface tension), which result in their movement toward the 
inflammatory center. This is only half the problem. The changes in the 
tissues themselves (changes in viscosity, for example), produced through 
the action of the excitant of the inflammation, also play a r61e. 



558 



(EDEMA AND NEPHRITIS 



influence of gravity, but in consequence of inequalities in the 
pressure exerted upon the surface of these elements, occasioned 
through inequalities in the stresses present in the tissues (brought 
about in turn through local changes in the water content of the 
lyophilic colloids comprising the tissues). And as the question 
of whether a mercury drop will 
enter a solidified gelatin, and the 
rate at which it will move about in 
this are matters that have to do 
with the surface tension relation- 
ships that exist between the mercury 
and the gelatin, and the viscosity of 
the gelatin (in its turn, affected by 
concentration, temperature, acids, 
bases and salts), so these same 
factors play a role in diapedesis as 
observed in the living organism. 

In Fig. 161 is shown how a 
mercury drop is unable to penetrate 
a stiffened gelatin (3 per cent) at 
room temperature. It may be rolled 
about on the surface of the gelatin 
without entering it. If the experi- 
ment is repeated at the same tem- 
perature, with a stiffened gelatin of 
a somewhat lower concentration, the 
mercury drop enters it and falls 
slowly to the bottom (Fig. 162, a, 
b, c). By turning the tube about 
(Fig. 163), the mercury drop moves 
in all directions through the stiff 

gelatin in which, of course, no holes exist, and in which none 
remain after the mercury has passed. 1 

The essential change in the gelatin, which makes such pene- 
trability possible in this experiment, was induced through regu- 




FlGURE 161. 



1 It is this property of colloids which explains why small wounds made 
in the living animal close immediately. The property of colloids, which 
gives them such great interest biologically, is the fact that they combine 
in one the properties of liquids (surface tension, viscosity, diffusion of dis- 
solved particles) with the properties of solids (maintenance of form). 



NEPHRITIS 559 

lation of the concentration. A similar change can be induced 
by raising the temperature somewhat (not to the point of melt- 
ing the gelatin, of course) or, in the presence of water, by adding 
a little acid. ' This approximates most closely the change that 
occurs in the body when in passive congestion, for example, a 




a be 
Figure 162. 



diapedesis into the cedematous tissues is noted. What happens 
under such circumstances can also be mimicked with some gelatin 
cakes and a few mercury drops. If one gelatin cake is placed 
in water, another in a dilute acid, the one in acid undergoes a 
swelling which after a time reaches a stage which readily admits 
of the passage of a mercury drop, while the control in water 
will not. 



560 



(EDEMA AND NEPHRITIS 



5. On the Origin and the Different Types of Tube Casts 

We have now to discuss how the abnormal acid content of 
the kidney in nephritis leads to the formation of casts. In this 
section we shall also learn how the various types of casts that 
are discovered in the urine in nephritis bear a simple relationship 
to each other; how, in fact, it is possible 
to convert one type of cast into another, 
and back again if we so choose, under the 
conditions found in the kidney and in the 
urine in nephritis. 

What must be the effect of the abnor- 
mal production or accumulation of acid in 
the kidney, so far as this problem of casts 
is concerned, may be determined in any 
one or all of several ways. We may simply 
leave the normal kidney, freshly removed 
from the body, to itself, protect it against 
evaporation, and study the effects of the 
postmortem development of acid in it. 
Or, we may slice the kidney into pieces 
and place them in water, or, finally, we 
may place such slices directly into slightly 
acidified water. The kidneys of guinea 
pigs and rabbits furnish excellent material, 
and it is on these that the following obser- 
vations were made. 

When we take a fresh kidney that has 
been cut across and squeeze it gently, we 
only see a little blood ooze from the blood Figure 163. 
vessels. If we scrape the surface and put a 
little of the scrapings on a slide, we find little more than some red 
blood corpuscles mixed with some granular material. In other 
words, it is difficult to obtain any kidney parenchyma cells — they 
do not separate easily from their attachments. The same kidney, 
preserved for several days, presents a different appearance. The 
surface may not be so glistening when cut, and on squeezing the 
organ, turbid points arise over the surface of the kidney which, 
when examined microscopically, are seen to be made up of epithe- 
lial cells which hav3 loosened from the kidney tubules. These 




NEPHRITIS 



561 



may be single, or joined together in groups, and with them 
are again found the red blood cells and the granular detritus 
that was observed in a scraping from the perfectly fresh 
kidney. 

A somewhat different picture is presented by the sections of 
kidney that are placed in water, Such tissues become gray more 
quickly than the tissues that do not come in contact with water, 
and develop an opaque appearance. The normal kidney markings 
gradually become obscured, and the tissues as a whole are seen to 
swell somewhat. The whole makes up the typical picture of that 
which the pathologists call cloudy swelling, and the nature of 
which was discussed in a foregoing section. The scraping from 
the surface of such a gray kidney shows a large number of free 
epithelial cells, which one has no difficulty in recognizing as com- 
ing from glomerular tufts and from the uriniferous tubules. In 
making the scraping one notices, moreover, that while vigorous 
scraping yielded little or nothing when applied to the healthy 
kidney, it is no trick at all to get an abundant amount of material 
from the surface of a kidney that has lain in water for a day or two. 
One notices, moreover, that the numerous epithelial cells are 
swollen and studded with granules. But beside the individual 
epithelial cells one notices groups of these, and then casts with 
rounded ends. One has no difficulty in recognizing these as du- 
plicates of the epithelial casts found in the urine in certain types 
of nephritis. 

But the most striking picture is that presented by the sec- 
tions of kidney thrown into a weak acid of some kind. In 
this the cloudy swelling of the slices of kidneys already described 
occurs very rapidly. A gentle scraping from the surface of a 
kidney slice, treated with dilute acid (n/500 lactic, for example), 
shows in several hours after immersion a granular detritus, separate 
epithelial cells, groups of epithelial cells and casts of various kinds 
(Figs. 164 and 165). When the kidney is simply gently squeezed 
and its surface touched to a slide, and this is then examined micro- 
scopically, one cannot escape the impression that he is examining 
a centrifuged urinary specimen from a case of acute nephritis. 
The epithelial cells, the epithelial casts, the granular casts are all 
there. One misses only the hyaline cast, but this can be promptly 
obtained by simply adding a little stronger acid to the specimen 
under the microscope, when the granular casts are seen to lose their 



562 



(EDEMA AND NEPHRITIS 




Figure 164. 



granules, swell somewhat 
more decidedly and become 
difficultly visible. Scat- 
tered nuclei may stick to 
the casts, but if enough 
acid is added, these too, 
go, so that only the 
greatly swollen, entirely 
hyaline " cylindroids " 
of some authors remain. 
Or, we can assure our- 
selves of a generous yield 
of hyaline casts and 
cylindroids from the 
start if we simply in- 
crease the acid concen- 
tration into which kidney 

slices are dropped or prolong their residence in the solu- 
tion. 

We can convert the granular casts into hyaline ones quite 
as easily through the addition of an alkali as through the addition 

of an acid, and if the 
kidney slices are from 
the first dropped into 
a dilute alkali, only 
hyaline casts are ob- 
tained. The hyaline 
casts produced 
through the acids can. 
be converted back 
into granular casts, 
if we wish, by simply 
running a little salt 
under the cover slip. 
A sulphocyanate is 
particularly good for 
this purpose, but if 
we wish to use a salt 
that is more " physio- 
logical " in nature, 





1 








'A .-. 

• 1/ . / 


m 


-A 



Figure 165. 



NEPHRITIS 



563 



sodium nitrate or sodium chlorid will do. The hyaline casts 
produced through alkalies can also be converted into gran- 
ular ones, though to accomplish this they must be treated with 
an equinormal acid. Why all these transformations are possible 
is, of course, readily intelligible when the experiments on cloudy 
swelling as detailed in the previous sections are recalled. 

In Fig. 166 is shown the appearance of a gentle scraping taken 
from a slice of kidney that had lain in water for several hours. 




Figure 166. 



A granular cell detritus and isolated casts characterize such a 
specimen. Nuclear fragments are prominent, and the epithelial 
cells may in places still be made out. The cells are granular. 
In Fig. 167, a, is shown a scraping similarly prepared from a slice 
of kidney that had lain in n/200 acetic acid for three hours. 
The cast formation (falling apart of the kidney) is a far more 
prominent feature. In the cast occupying the central point in 
the photomicrograph remnants of an epithelial structure are 
still present. In the casts lying above this all evidences of nuclear 
structure have disappeared. They are filled with fine granules. 



564 



(EDEMA AND NEPHRITIS 



When these casts were treated with a stronger solution of acetic 
acid they became hyaline, as shown in Fig. 167, b. 1 

It is clear, therefore, that under the influence of a little acid 
the kidney drops apart into its morphological elements. While 
these are firmly cemented together in the healthy kidney (as 
witness the attempt to obtain them by scraping the surface of 
the kidney with a knife), they are separated with the greatest 
ease after the kidney has lain in acid for a while. The answer 




Figure 167. 

to why the kidney falls apart as it does under the influence of 
acid it is needless to discuss, but the view that some of the (col- 
loid) " cement substances " are more easily " soluble " or more 
easily " digested " in weak acids than other portions of the kidney 
at once suggests itself. Such a view finds support in our previous 
considerations of albuminuria and in the fact, easily observed in 

1 Casts lose their granules and appear hyaline to ordinary microscopic 
vision before they become hyaline photographically. This is easily explained 
by the optical behavior of colloids. As Wolfgang Ostwald has emphasized, 
the ultraviolet rays affecting the photographic plate are still refracted (and 
the picture appears granular) by particles too small to change the path of 
the longer rays of ordinary white light. 



NEPHRITIS 



565 



these experiments, that the solutions in which the kidney slices 
lie, come to contain, with time, progressively larger amounts of 
albumin. That some constituents of the kidney (or of any other 
organ) are more readily soluble in an acid than are others, is 
clearly enough evident under the microscope. The nuclei of 
the cells still retain their outlines, for example, in concentrations 
of acid in which the protoplasm generally has become entirely 
hyaline. The action of the acid could be aided and abetted, 
of course, by the various substances which in their action on the 
body colloids act like acids, including the enzymes. 

What is important to us, from the standpoint of the theory 
of nephritis, is the way in which the kidney falls apart. The epi- 
thelial cells tend to stick together while they separate in mass from 
their supporting membrane. This marks the origin of the urinary 
cast which, in clinical cases, is washed down into the bladder by 
the force of the secreted urine. 

These simple facts regarding the origin of casts, and the con- 
ditions under which the one type may be converted into another, 
are not without clinical significance. In treatises on medicine 
and in works on clinical diagnosis much has been said, not 
only regarding the importance of the appearance of casts in the 
urine, but of the significance of the different kinds of casts. It 
seems to me that the experiments just detailed urge caution 
upon one in drawing too sweeping conclusions from such data. 
So far as mere numbers of casts are concerned, it requires no spe- 
cial emphasis to realize that great numbers of casts present in the 
urine at one time, while indicative of a more extensive involve- 
ment of the kidney parenchyma at that time may not be as sig- 
nificant as a lesser number present over longer periods of time. 
The aggregate destruction may in the latter case, of course, be 
much greater than in the former (a condition further modified 
in the living organism by the rate and quantity of the regenera- 
tion occurring in the kidney). 

In judging of the meaning of the character of the cast, whether 
epithelial, granular, or hyaline, one must be exceedingly care- 
ful. We have seen that the epithelial cast is readily convertible 
into either the granular or the hyaline, depending upon how 
much acid is present and the length of time that it is allowed 
to act; and the hyaline, we have seen, can be reconverted into 
the granular. The thought might suggest itself that we use 



566 



CEDE MA AND NEPHRITIS 



the nature of the cast as an index of the acid concentration 
in the kidney and so as a measure of the intensity of the 
nephritis. But this may not be done, for we know from autopsy 
findings that a nephritis need not affect all the parts of a kid- 
ney equally, or at the same time, and the urine represents the 
mixed product of the whole kidney. Moreover, the urine itself 
varies so in composition under different (physiological) cir- 
cumstances that it may alter the character of the cast in its 
passage through the ureter and bladder, no matter what its 
nature when it left the kidney. A highly acid urine would on 
the whole tend to yield granular or, if sufficiently high, hyaline- 
casts. An alkaline urine would tend to yield only hyaline casts. 
On the other hand, the salts of the urine would tend to counteract 
the acid and make the casts not only smaller (loss of water by 
the colloid) but more granular (precipitation of the colloid). 
One can easily satisfy himself of these facts by providing him- 
self with casts from a clinical case of acute nephritis, or from 
such kidneys as I have described, and examining them under 
the microscope, while a little acid, or this in conjunction with 
various salts, is allowed to run under the coverslips of the 
preparations. 

In concluding this section it is well to revert for a moment 
to the question of albuminuria. It is possible to test the idea 
that albuminuria results from a " solution " of the proteins 
of the kidney under the influence of an acid in these experiments 
on the formation of casts. If we take a perfectly fresh kidney 
from either a rabbit or a guinea pig, cut it into several slices, 
and wash the pieces a few times in water or a " physiological " 
0.9 per cent XaCl solution, so as to get rid of the blood, we find 
thereafter that the wash water gives little or no reaction for 
albumin. But if we permit the pieces of kidney to lie in the 
wash water until next day, we have no difficulty in getting the 
albumin reaction. Still more rapidly do we get it if we immerse 
the washed slices of kidney from the start in a weak acid solution. 
If we pipette off the sediment found about the kidney pieces and 
examine this under the microscope, we find at the same time 
various kinds of casts. But the albumin is not simply due 
to these, for we continue to get a marked albumin reaction after 
careful filtration. 



NEPHRITIS 



567 



VII 

SOME RESPONSES TO CRITICISM 

There has been much that is foolish written against the simple 
conclusions outlined in the foregoing pages according to which the 
tissues of living organisms owe their water holding power to the 
fact that they contain hydrophilic colloids, that they become 
cedematous whenever such water-holding power is increased (as 
through the presence of abnormally high amounts of acids) and that 
in the " solution " or liquefaction of such colloids (also under the 
influence of acids and similarly acting substances) is to be found 
the essential mechanism of albuminuria. Many of these criticisms 
rest upon a misreading or an actual violation of what I have written 
and to such it is mere futility to respond. It is the purpose of 
these paragraphs to revert to the oft-repeated objection that an 
abnormal production or accumulation of acids in a cell, tissue or 
organ can not be a potent cause of oedema, albuminuria, etc., 
because the tissues contain phosphates or other " buffer " salts 
which have the power of taking up considerable amounts of either 
acid or alkali without change in " hydrogen ion acidity." 1 Aside 
from the fact, often pointed out before, that such buffer action is 
not unlimited in amount, that there is a vast difference between 
our constantly reiterated " acid content " of tissues and their 
hydrogen ion concentration, that the physiological action of even 
pure acids nowhere parallels their electrolytic dissociation, and that 
even with extreme variations in acid content there may be little 
change in hydration capacity if various neutral salts are present, the 
following data show that from a given low point, even in the presence 
of such "buffer" salts, there is a progressive increase in water absorp- 
tion by various proteins and a progressive tendency to liquefy or go into 
solution with every increase in the acid or alkali content of the mixture. 

1. On the Swelling of Gelatin in Polybasic Acids and their Salts 2 

Dried gelatin discs prepared in the accepted fashion 3 served 
as the material upon which to test out the effects of different poly- 

' 1 See, for example, Max Koppel: Deut. Arch. klin. Med., 112, 594 
(1913); L. J. Henderson, W. W. Palmer and L. H. Newburgh: Jour. 
Pharm. Exp. Therap., 5, 449 (1914). 

2 Martin H. Fischer and Marian O. Hooker: Science, 46, 189 (1917); 
Jour. Am. Chem. Soc, 40, 272 (1918. 

3 See page 75. 



568 



(EDEMA AND NEPHRITIS 



basic acids and their salts. For the polybasic acids we chose 
phosphoric and carbonic because of their importance in the animal 




body, and citric because of its great role in the plant economy. 
From the standardized solutions of these acids and of sodium 
hydroxid were then made the necessary primary, binary or ternary 



NEPHRITIS 



569 



salts, by mixing the acid and alkali together in the theoretically 
necessary amounts. 




The figures and tables are largely self-explanatory. The 
changes in weight (water absorption) of the gelatin discs at the end 
of different periods are calculated in terms of the original dry 
weight of the disc taken as unity. 



570 



(EDEMA AND NEPHRITIS 




and trisodium phosphates and to discover how long a time is 
necessary before this water absorption is approximately complete. 



NEPHRITIS 



571 



The results of three such experiments are shown in the curves of 
Figs. 168, 169 and 170, as well as in Tables CV, CVI and CVII, 
which contain the data from which the curves are drawn. 

TABLE CV 



Gelatin — Monosodium phosphate 



Dry weight of 
gelatin disc. 


0.311 


0.312 


0.312 


0.314 


0.310 


Solution 


5 cc. m/1 
NaH 2 P04 
+95 cc. H 2 


15 cc. m/1 
NaH 2 P04 
+85 cc. H2O 


25 cc. m/1 
NaH 2 P04 
+75 cc. H2O 


50 cc. m/1 
NaH 2 P0 4 
+50 cc. H 2 


100 cc. H2O 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


18 
24 
42 
48 
66 
89 


7.31 
7.71 
8.27 
8.50 
8.65 
9.03 
I 


7.75 
8.25 
9.00 
9.20 
9.37 
9.87 
II 


7.73 
8.16 
8.83 
9.12 
9.25 
9.73 
III 


7.12 
7.55 
8.20 
8.38 
8.60 
9.00 
IV 


7.30 
7.60 
8.45 
8.90 
9.80 
11.91 
H2O 






TABLE 


CVI 








Gelatin — Disodium phosphate 




Dry weight of 
gelatin disc. 


0.317 


0.317 


0.319 


0.319 


0.315 


Solution 


5 cc. m/1 
Na 2 HP04 
+95 cc. H2O 


15 cc. m/1 
Na2HP0 4 
+85 cc. H2O 


25 cc. m/1 
Na 2 HP04 
+75 cc. H2O 


50 cc. m/1 
Na 2 HP0 4 
+50 cc. H2O 


100 cc. H2O 


Hours in the 
solution* 


Gain in parts of one part of gelatin. 


18 
24 
42 
48 
66 
89 


9.10 
9.74 
10.65 
10.91 
11.16 
11.65 
I 


8.57 
9.16 
10.08 
10.32 
10.70 
11.22 
II 


7.80 
8.30 
9.06 
9.30 
9.63 
10.20 
III 


5.60 
5.91 
6.40 
6.56 
6.74 
7.24 
IV 


6.84 
7.41 
8.20 
8.60 
10.43 
11.22 
H2O 



As evidenced in Fig. 168, gelatin swells little more or little less 
in any solution of monosodium phosphate between the concen- 
trations of m/20 and m/2 than it does in pure water. Fig. 169 
shows that disodium phosphate in its lower concentrations tends 
to increase the swelling of gelatin. A maximal swelling is observed 



572 



(EDEMA AND NEPHRITIS 



TABLE CVII 



Gelatin — Trisodium phosphate 



Dry weight of 
gelatin disc. 


0.321 


0.322 


0.322 


0.323 


0.320 


Solution 


5 cc. m/1 
Na 3 P04 
+95 ec. H 2 


15 cc. m/1 
NasPO* 
+85 cc. H 2 


25 cc. m/1 

NasPO* 
+75 cc. H2O 


50 cc. m/1 

NasP04 
+50 cc. H2O 


100 cc. H 2 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


18 
24 
42 
48 
66 
89 


12.44 
13.97 
17.31 
18.26 
20.93 
22.46 
I 


10.30 
11.67 
15.28 
16.61 
19.71 
22.22 
II 


8.44 
9.62 
12.94 
14.10 
17.20 
21.80 
III 


3.77 

4.06 
4.63 
4.83 
5.10 
5.55 
IV 


5.32 
6.52 
7.75 
8.20 
9.21 
10.72 
H2O 



in the least concentrated solution of this salt. With increasing 
concentration the amount of swelling decreases so that by the time 
the m/2 disodium phosphate solution is reached, the swelling of 
the gelatin is distinctly less than in pure water. A similar rule 
holds for like concentrations of trisodium phosphate, as shown in 
Fig. 170. Gelatin swells distinctly more in low concentrations 
of trisodium phosphate than in water, though reverse conditions 
come to obtain when the concentration of the phosphate is suffi- 
ciently increased. 

The curves of Fig. 168, 169 and 170 suffice to show that gelatin 
practically attains its ultimate degree of swelling in a phosphate 
solution at the end of 24 to 48 hours. We therefore settled upon 
such approximate periods for the next series of experiments in 
which we sought to discover the amount of swelling shown by gela- 
tin when immersed in solutions varying from pure phosphoric 
acid, on the one hand, through mono-, di- and trisodium phos- 
phate mixtures to pure sodium hydroxid on the other. It was our 
purpose in this series to see how the amount of swelling fared 
as more and more of the initially pure phosphoric acid was replaced 
by the mono-, di- or trisodium salt. The result is shown in Table 
CVIII and Fig. 171. The curves show the amounts of swelling at 
the end of 18 and 24 hours. The low point in the curve indicative 
of least swelling is representative of the effects observed in the 
phosphate mixture numbered 6 in Table CVIII. As readily 



NEPHRITIS 



573 



TABLE CVIII 



Gelatin — Phosphoric acid to phosphates, to sodium hydroxid 



Dry weight o 
gelatin disc. 


f 0.363 


0.367 


0.367 


0.368 


0.368 


0.368 


0.368 


Solution 


10 cc. n/1 
H3PO4 
+90 cc. 
H2O 


8 cc. n/1 
H3PO4 
+2 cc. 

m/1 
NaH 2 PO 
+90 cc. 

H 2 


6 cc. n/1 
H3PO4 
+4 cc. 
m/1 
NaH 2 PG 
+90 cc. 
H2O 


4 cc. n/1 
H3PO4 
+6 cc. 
m/1 
NaH 2 P0 4 
+90 cc. 
H 2 


2 cc. n/1 
H3PO4 
+8 cc. 
m/1 
NaH 2 P0 4 
+90 cc. 
H 2 


10 cc. m/1 
NaH 2 P0 4 
+90 cc. 
H2O 


8 cc. m/1 
NaH 2 P04 
+2 cc. 
m/1 
Na 2 HP04 
+90 cc. 
H2O 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


18 

24 


36.51 
44.55 
(1) 


29.14 
35.16 

(2) 


25.60 
29.70 

(3) 


20.21 
24.23 

(4) 


16.24 
19.86 

(5) 


7.42 
8.28 

(6) 


8.21 
9.31 
(7) 


Dry weight of 
gelatin disc. 


0.369 


0.371 


0.371 


0.377 


0.382 


0.383 


0.383 


Solution 


6 cc. m/1 
NaH 2 P04 
+4 cc. 

m/1 
Na 2 HP0 4 
+ 90 cc. 

H2O 


4 cc. m/1 
NaH 2 P04 
+6 cc. 
m/1 
Na 2 HP04 
+90 cc. 
H 2 


2 cc. m/1 
NaH 2 POi 
+8 cc. 
m/1 
Na 2 HP04 
+90 cc. 
H 2 


10 cc.m/1 
Na 2 HP0 4 
+90 cc. 
m/1 
H2O 


8 cc. m/1 
Na 2 HP0 4 
+2 cc. 
m/1 
Na 3 P04 
+90 cc. 
H2O 


6 cc. m/1 
Na 2 HP04 
+4 cc. 
m/1 
Na 3 P04 
+90 cc. 
H2O 


4 cc. m/1 
Na 2 HP0 4 
+6 cc. 
m/1 
Na 3 P0 4 
+90 cc. 
H2O 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


18 
24 


8.44 
9.49 
(8) 


8.50 
9.56 
(9) 


8.90 
10.05 
(10) 


8.61 
9.85 
(ID 


9.52 
11.04 
(12) 


10.86 
13.09 
(13) 


10.51 
12.63 
(14) 


Dry weight of 
gelatin disc. 


0.383 


0.384 


0.385 


0.389 


0.391 


0.393 


0.384 


Solution 


2 cc. m/1 
Na 2 HP04 
+8 cc. 

m/1 
Na 3 P04 
+90 cc. 

H 2 


10 cc. m/1 
Na 3 P0 4 
+90 cc. 
H2O 


8 cc. m/1 
Na.3P04 
+2 cc. 
n/1 
NaOH 
+90 cc. 
H2O 


6 cc. m/1 
NasP04 
+4 cc. 
n/1 
NaOH 
+90 cc. 
H2O 


4 cc. m/1 
Na 3 P04 
+6 cc. 
n/1 
NaOH 
+90 cc. 
H2O 


2 cc. m/1 
Na 3 P04 
+8 cc. 
n/1 
NaOH 
+90 cc. 
H 2 


100 cc. 
H2O 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


18 

24 


10.55 
12.81 
(15) 


12.60 
17.45 
(16) 


14.51 
21.45 
(17) 


17.27 
dissolved 
(18) 


20.22 
dissolved 
(19) 


dissolving 
dissolving 
(20) 


6.86 
7.77 
(H2O) 



574 (EDEMA AND NEPHRITIS 



apparent, every increase in acid content to the left of this point 
is followed by increased swelling and the same is true for every 
increase in alkali content to the right of this point. 

It is an interesting fact that the hydrogen ion concentration of 

Solution 6 is about that in- 
dicated by the turning point 
of methyl red (10~ 6 C H ). 
While we would not have it 
thought that the behavior 
of gelatin is at once to be 
paralleled with that of our 
body proteins, it is a fact 
that clinical observation in- 
dicates that urinary hydrogen 
ion acidities approach an 
unsafe height when they be- 
gin to lie persistently above 
this point. 1 

Since the concentration 
of the phosphate mixtures 
employed in the experiments 
just described is relatively 
high (m/10), we did a second 
series at a concentration ap- 
proximately that of the phos- 
phates in the human body. 
The results are shown in Fig. 
172 and Table CIX. The 
general shapes of the two 
curves which again represent 
the amounts of swelling at- 
tained in the different solu- 
SoiutionNo.5 io is tions at the ends of 18 and 

Figure 171. 42 hours are identical with 

those shown in Fig. 171. It 
is of interest to point out that the low point in the swelling curves 
representative of the effects of this more dilute phosphate 
mixture falls below the amount of swelling attained in pure 

1 Martin H. Fischer: Trans. Assoc. Am. Phys., 27, 630 (1912); also 
page 773. 




NEPHRITIS 



575 




water. There is, however, a relatively greater swelling as we 
move from this minimal point either in the direction of an 
increased acid or increased alkali content of the solutions, even 



576 



(EDEMA AND NEPHRITIS 



TABLE CIX 

Gelatin — Phosphoric acid to phosphates, to sodium hydroxid 



Dry weight 
of gelatin 
disc. 


0.401 


0.402 


0.403 


0.404 


0.406 


0.409 


0.409 


Solution 


1 cc. 
n/1 
HsP04 
+99 cc 
H 2 


0.8 cc. 

n/1 
HsP04 
+0.2 cc. 

m/1 
NaH 2 P04 
+99 cc. 
H2O 


0.6 cc. 

n/1 
H3PO4 
+0.4 cc. 

m/1 
NaH 2 P04 
+99 cc. 
H2O 


0.4 cc. 

n/1 
H3PO4 
+0.6 cc. 

m/1 
NaH 2 P04 
+99 cc. 
H2O 


0.2 cc. 

n/1 
H3PO4 
+0.8 cc. 

m/1 
NaH 2 P04 
+99 cc. 
H2O 


1 cc. 
m/1 
NaH 2 P04 
+99 cc. 
H2O 


. 8 cc. 
m/1 
NaHzPOi 
+0.2 cc. 

m/1 
Na 2 HP04 
+99 cc. 
H2O 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


18 

42 


44.00 
55.97 
(1) 


37.60 
53.97 

(2) 


31.02 
42.84 

(3) 


22.94 
32.73 

(4) 


10.49 
17.54 

(5) 


5.15 
6.88 
(6) 


7.65 
9.14 
(7) 


Dry weight 
of gelatin 
disc. 


0.409 


0.409 


0.411 


0.414 


0.414 


0.414 


0.417 


Solution 


0.6 cc. 
m/1 
NaH 2 P04 
+0.4 cc. 

m/1 
Na 2 HP0 4 
+99 cc. 
H2O 


0.4 cc. 
m/1 
NaH 2 P04 
+0.6 cc. 

m/1 
Na 2 HP04 
+99 cc. 
H2O 


0.2 cc. 

m/1 
NaH 2 P04 
+0.8 cc. 

m/1 
Na 2 HP04 
+99 cc. 
H2O 


1 cc. 

m/1 
Na 2 HP04 
+99 cc. 

H2O 


0.8 ce. 

m/1 
Na 2 HP04 
+0.2 cc. 

m/1 
Na 3 P0 4 
+99 cc. 

H2O 


0.6 cc. 

m/1 
Na 2 HP0 4 
+0.4 cc. 

m/1 
Na 3 P0 4 
+99 cc. 
H2O 


0.4 cc. 

m/1 
Na 2 HP0 4 
+0.6 cc. 

m/1 
Na 3 P0 4 
+99 cc. 

H2O 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


18 
42 


8.00 
9.80 
(8) 


8.42 
10.24 

(9) 


8.55 
10.50 
(10) 


8.48 
10.31 
(ID 


9.20 
10.98 
(12) 


11.64 
12.90 
(13) 


11.42 
13.26 
(14) 



Dry weight 


















of gelatin 


0.419 


0.420 


0.421 


0.424 


0.425 


0.425 


0.426 


0.408 


disc. 




















0.2 cc. 


1 cc. 


0.8 cc. 


0.6 cc. 


0.4 cc. 


0.2 cc. 


1 cc. 


100 cc. 




m/1 


m/1 


m/1 


m/1 


m/1 


m/1 


n/1 


H2O 




Na 2 HP0 4 


Na 3 P0 4 


Na 3 P04 


Na 3 P0 4 


Na 3 P0 4 


Na 3 P0 4 


NaOH 




Solution 


+0.8 cc. 


+99 cc. 


+0.2 cc. 


+0.4 cc. 


+0.6 cc. 


+0.8 cc. 


+99 cc. 






m/1 


H 2 


n/1 


n/1 


n/1 


n/1 


H2O 






Na a P04 




NaOH 


NaOH 


NaOH 


NaOH 








+99 cc. 




+99 cc. 


+99 cc. 


+99 cc. 


+99 cc. 








H2O 




H2O 


H2O 


H2O 


H2O 







Hours in the 
solution. 



Gain in parts of one part of gelatin. 



15.20 


17.37 


17.72 


17.88 


21.57 


25.08 


26.65 


6.09 


16.44 


18.77 


18.74 


18.84 


21.74 


25.43 


27.06 


7.50 


(15) 


(16) 


(17) 


(18) 


(19) 


(20) 


(21) 


(H2O) 



NEPHRITIS 



577 



though the proportions in the various mixtures are identical with 
those used in the experiments of Table CVIII. The absolute 



45 








40 




Gelatin 

Disodium Phosphate +Fhosphori , G^Acid or Sodium Hydroxid 


35 








80 








25 
20 








15 








10 




\ \ 45 Hours ^ 




5 


O *22Hours 

H 2 

1 1 I 1 


Sh 2 o 

1 1 



Solution No. 5 10 15 20 25 30 

Figure 173. 

amounts of swelling in the acid and alkaline extremes of these 
more dilute phosphate mixtures are distinctly higher than in the 
more concentrated phosphate series previously described. 

In the experiments listed in Tables CVIII and CIX, the molar 



578 



(EDEMA AND NEPHRITIS 



concentration of the phosphate is the same throughout. While 
the_ curves of Figs. 171 and 172 show that every increase in the 
acid or alkali content of the phosphate mixture on either side of a 
low point is followed by an increased water absorption on the part 
of the immersed protein, it might be argued that such conditions 
do not obtain in the living organism where, it might be insisted, 
we begin with a definite concentration of a certain phosphate and 
then see an acid or an alkali added to this. That under such cir- 
cumstances we also get a progressive increase in swelling as either 




Solution No.5 10 15 ^ 20 

Figure 174. 



the acid or alkali content of the mixture rises is shown in Figs. 173 
and 174. and Tables CX and CXI. The first of these figures and 
tables begins with a fixed concentration of disodium phosphate 
(m/100), the second, with the same concentration of the mono- 
sodium salt. 

A set of experiments was next made by beginning with a fixed 
concentration of acid (3/100 n) and adding to this progressively 
greater amounts of alkali. Under such circumstances there are 
seen, of course, the double effects of decrease in concentration of 
free acid with increase in amount of phosphate present, The 
general shape of the water absorption curve as shown in Fig. 175 and 
Table CXII is, however, that familiar to us from the previous 



NEPHRITIS 



579 



Gelatin- 



TABLE CX 

-Disodium phosphate -{-phosphoric acid or sodium hydroxid 



Dry wt. of 
gelatin disc. 


0.443 


0.441 


0.438 


0.437 


0.436 


0.434 


0.434 


Solution 


100 cc. 
H2O 


2 cc. 

n/1 
H3PO4 
+98 cc. 

H2O 


4 cc. 

m/4 
Na 2 HP0 4 
+2.0 cc. 

n/1 
H3PO4 
+94 cc. 

H 2 


4 cc. 

m/4 
Na 2 HP04 
+ 1.9 cc. 

n/1 
H3PO4 
+94.1 cc. 

H2O 


4 cc. 
m/4 
Na 2 HP0 4 
+1.8 cc. 

n/1 
H3PO4 
+94.2 cc. 
H2O 


4 cc. 

m/4 
Na 2 HP0 4 
+1.7 cc. 

n/1 
H3PO4 
+94.3 cc. 

H2O 


4 cc. 

m/4 
Na 2 HP0 4 
+ 1.6 cc. 

n/1 
H 3 P0 4 
+94.4 cc 

H 2 04 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


22 
45 


6.28 
7.20 
(H2O) 


43.00 
50.40 
(1) 


23.70 
28.34 
(2) 


21.70 
26.50 
(3) 


20.73 
25.36 
(4) 


20.80 
25.25 

(5) 


19.14 
23.47 
(6) 


Dry wt. of 
gelatin disc. 


0.434 


0.433 


0.433 


0.431 


0.431 


0.423 


0.422 


Solution 


4 cc. 

m/4 
Na 2 HP04 
+1.5 cc. 

n/1 
H3PO4 
+94.5 cc. 

H2O 


4 cc. 
m/4 
Na 2 HP04 
+1.4 cc. 

n/1 
H3PO4 
+94.6 cc. 
H2O 


4 cc. 
m/4 
Na 2 HP04 
+ 1.3 cc. 

n/1 
H3PO4 
+94.7 cc. 
H2O 


4 cc. 
m/4 
Na 2 HP04 
+1.2 cc. 

n/1 
H3PO4 
+94.8 cc. 
H 2 


4 cc. 
m/4 
Na 2 HP04 
+1.1 cc. 

n/1 
H3PO4 
+94.9 cc. 
H 2 


4 cc. 
m/4 
Na 2 HP0 4 
+ 1.0 cc. 

n/1 
H3PO4 
+95 cc. 
H2O 


4 cc. 

m/4 
Na 2 HP04 
+0.9 cc. 

n/1 
H3PO4 
+95.1 cc. 

H 2 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


22 
45 


17.11 
21.17 
(7) 


14.23 
19.00 

(8) 


11.00 
15.00 
(9) 


8.47 
11.10 
(10) 


6.70 
8.00 
(11) 


6.28 
7.10 
(12) 


6.22 
7.37 
(13) 


Dry wt. of 
gelatin disc. 


0.421 


0.420 


0.419 


0.419 


0.416 


0.415 


0.414 


Solution 


4 cc. 

m/4 
Na 2 HP04 
+0.8 cc. 

n/1 
H3PO4 
+95.2 cc. 

H2O 


4 cc. 
m/4 
Na 2 HP04 
+0.7 cc. 

n/1 
H3PO4 
+95.3 cc. 
H2O 


4 cc. 
m/4 
Na 2 HP04 
+0.6 cc. 

n/1 
H3PO4 
+95.4 cc. 
H2O 


4 cc. 
m/4 
Na 2 HP04 
+0.5 cc. 

n/1 
H3PO4 
+95.5 cc. 
H2O 


4 cc. 
m/4 
Na 2 HP04 
+0.4 cc. 

n/1 
H3PO4 
+95.6 cc. 
H 2 


4 cc. 

m/4 
Na 2 HP04 
+0.3 cc. 

n/1 
H3PO4 
+95.7 cc. 

H 2 


4 cc. 

m/4 
Na 2 HP04 
+ 0.2 cc. 

n/1 
H3PO4 
+95.8 cc. 

H 2 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


22 
45 


7.00 
8.03 
(14) 


7,33 
8.34 
(15) 


7.50 
9.14 
(16) 


7.80 
9.07 
(17) 


7.90 
9.08 
(18) 


8.00 
9.10 
(19) 


8.16 
9.30 
(20) 



- 



580 (EDEMA AND NEPHRITIS 



TABLE CX— Concluded 



Dry wt. of 
gelatin disc. 


0.413 


0.413 


0.405 


0.406 


0.406 


0.407 


0.407 


Solution 


4 cc. 

m/4 
Na 2 HP0 4 
+0.1 cc. 

n/1 
H3PO4 
+95.9 cc. 

H2O 


4 cc. 

m/4 
Na 2 HP04 
+96 cc. 

H2O 


4 cc. 

m/4 
Na 2 HP04 
+96 cc. 

H2O 


4 cc. 

m/4 
Na 2 HP04 
+0.1 cc. 

n/1 
NaOH 
+95.9 cc. 

H2O 


4 cc. 

m/4 
Na 2 HP04 
+0.2 cc. 

n/1 
NaOH 
+95.8 cc. 

H2O 


4 cc. 
m/4 
Na 2 HP04 
+0.3 cc. 

n/1 
NaOH 
+95.7 cc. 
H2O 


4 cc. 
m/4 
Na 2 HP04 
+0.4 cc. 
- n/1 
NaOH 
+95.6 cc. 
H2O 


Hrs. in the 
solution. 


Gain in parts of one part in gelatin. 


22 
45 


8.45 
9.70 
(21) 


8.68 
10.06 
(22) 


7.63 
8.72 
(23) 


8.03 
9.20 
(24) 


8.57 
9.82 
(25) 


8.60 
9.70 
(26) 


10.29 
11.05 
(27) 


Dry wt. of 
gelatin disc. 


0.407 


0.408 


0.408 


0.409 


0.410 


0.411 


0.412 


Solution 


4 cc. 
m/4 
Na 2 HP0 4 
+0.5 cc. 

n/1 
NaOH 
+95.5 cc. 
H2O 


4 cc. 
m/4 
Na 2 HP04 
+0.6 cc. 

n/1 
NaOH 
+95.4 cc. 
H2O 


4 cc. 
m/4 
Na 2 HPO 
+0.7 cc. 

n/1 
NaOH 
+95.3 cc. 
H2O 


4 cc. 
m/4 
Na 2 HP04 
+0.8 cc. 

n/1 
NaOH 
+95.2 cc. 
H2O 


4 cc. 
m/4 
Na 2 HP04 
+0.9 cc. 

n/1 
NaOH 
+95.1 cc. 
H2O 


4 cc. 

m/4 
Na 2 HP04 
+ 1.0 cc. 

n/1 
NaOH 
+95 cc. 

H2O 


100 cc. 
H2O 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


22 
45 


11.21 
11.80 

(28) 


12.65 
12.72 
(29) 


13.41 
13.65 
(30) 


14.40 
15.40 
(31) 


14.57 
15.70 

(32) 


14.87 
14.81 

(33) 


6.04 
6.82 
(H2O) 



experiments. A low point is again found in the middle of the curve 
when one-third of the replaceable hydrogen of the phosphoric 
acid has been neutralized by alkali, in other words, when we deal 
with a solution which is practically pure monosodium phosphate. 
Addition of more alkali leads to increased swelling up to the high 
point at the right of the curve which represents the theoretically 
pure solution of trisodium phosphate. 

A final series of phosphate experiments is shown in Fig. 176 and 
Table CXIII. Here a fixed amount of alkali (3/100 n) was neu- 
tralized by adding gradually increasing amounts of phosphoric 
acid. There are shown, in other words, the effects of simultaneous 
reduction of alkali with increase in amount of phosphate present. 



NEPHRITIS 



581 



TABLE CXI 

Gelatin — Monosodium phosphate, with increasing amounts of sodium hydroxid 



Dry wt. of 
gelatin disc 



Solution 



0.388 



1 cc. 

m/l 
NaH 2 P0 4 
+99 cc. 

H 2 



0.390 



1 cc. 

m/l 
NaH 2 P0 4 
+0.1 cc. 

n/1 
NaOH 
4-98.9 cc. 

H 2 



0.391 



1 cc. 

m/l 
NaH 2 PO< 
+0.2 cc. 

n/1 
NaOH 
+98.8 cc. 

H 2 



0.392 



1 cc. 

m/l 
NaH 2 PO< 
+0.3 cc. 

n/1 
NaOH 
+98.7 cc. 

H 2 



0.392 



1 cc. 

m/l 
Na'H 2 P04 
+0.4 cc. 

n/1 
NaOH 
+98.6 cc. 

H 2 



0.393 



1 cc. 

m/l 
NaH 2 P04 
+0.5 cc. 

n/1 
NaOH 
+98.5 cc 

H 2 



0.393 



1 cc. 

m/l 
NaH;P0 4 
+0.6 cc. 

n/1 
NaOH 
+98.4 cc. 

H 2 



0.393 



1 cc. 

m/l 
NaH 2 P0 4 
+0.7 cc. 

n/1 
NaOH 
+98.3 cc. 

H 2 



Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


20 
44 


5.90 
6.78 
(1) 


6.90 
8.10 

(2) 


7.11 

8.44 
(3) 


7.11 

8.56 
(4) 


7.65 
9.00 

(5) 


7.47 

8.80 
(6) 


7.50 
9.00 
(7) 


7.53 
8.83 
(8) 


Dry wt. of 
gelatin disc. 


0.394 


0.395 


0.395 


0.397 


0.398 


0.400 


0.400 


Solution 


1 cc. 
m/l 
NaH 2 P04 
+0.8 cc. 

n/1 
NaOH 
+98.2 cc. 
H 2 


1 cc. 
m/l 

NaH 2 P0 4 
+0.9 cc. 

n/1 
NaOH 
+98.1 cc. 
H2O 


1 cc. 

m/l 
NaH 2 P04 
+1.0 cc. 

n/1 
NaOH 
+98 cc. 

H 2 


1 cc. 

m/l 
NaH 2 P0 4 
+1.1 cc. 

n/1 
NaOH 
+97.9 cc. 

H 2 


1 cc. 

m/l 
NaH 2 P04 
+1.2 cc. 

n/1 
NaOH 
+97.8 cc. 

H2O 


1 cc. 

m/l 
NaH 2 P04 
+ 1.3 cc. 

n/1 
NaOH 
+97.7 cc. 

H2O 


1 cc. 
m/l 
NaH 2 P04 
+1.4 cc. 

n/ 
NaOH 
+97.6 cc. 
H2O 


Hrs. in the 
solution. 


Gain in parts in one part of gelatin 


20 
44 


8.02' 
9.45 
(9) 


8.12 
9.57 
(10) 


8.17 
9.70 
(11) 


8.37 
9.84 
(12) 


8.20 
9.60 
(13) 


9.80 
11.03 
(14) 


10.24 
11.30 
(15 ) 


Dry wt. of 
gelatin disc. 


0.401 


0.403 


0.403 


0.403 


0.404 


0.405 


0.405 


0.405 


Solution 


1 cc. 

m/l 
NaH 2 P0 4 
+1.5 cc. 

n/1 
NaOH 
+97.5 cc. 

H2O 


1 cc. 

m/l 
NaH 2 P0 4 
+1.6 cc. 

n/1 
NaOH 
+97.4 cc. 

H2O 


1 cc. 

m/l 
NaH 2 P0 4 
+1.7 cc. 

n/1 
NaOH 
+97.3 cc. 

H2O 


1 cc. 

m/l 
NaH 2 P04 
+1.8 cc. 

n/1 
NaOH 
+97.2 cc. 

H2O 


1 cc. 
m/l 
NaH 2 P04 
+1.9 cc. 
n/1 
NaOH 
+97.1 cc. 
H2O 


1 cc. 

m/l 
NaH 2 P04 
+2.0 cc. 

n/1 
NaOH 
+97 cc. 

H2O 


2.0 cc. 

n/1 
NaOH 
+98 cc. 

H2O 


100 cc. 
H2O 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


20 
44 


12.00 
12.54 
(16) 


12.51 
12.94 
(17) 


12.28 
12.56 
(18) 


14.04 
14.10 
(19) 


14.42 
14.47 
(20) 


IS. 55 
15.42 
(21) 


19.65 
23.91 
(22) 


6.13 
7.06 
(H2O) 



(EDEMA AND NEPHRITIS 




5 - 



Solution No. 5 



i 



10 15 20 25 

Figure 175. 



30 



NEPHRITIS 



583 



TABLE CXII 



Gelatin — Phosphoric acid with increasing amounts of sodium hydroxid 



Dry wt. of 
gelatin disc 


0.343 


0.343 


0.345 


0.347 


0.360 


0.363 


0.365 


0.367 


Solution 


3 cc 

n/1 
H3PO4 
+97 cc. 

H2O 


3 cc. 
n/1 
H3PO4 
+0.1 cc. 

n/1 
NaOH 
+96.9cc. 
H 2 O s 


3 cc. 
n/1 
H3PO4 
+0.2 cc. 

n/1 
NaOH 
+96.8cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+0.3 cc. 

n/1 
NaOH 
+96.7cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+0.4 cc. 

n/1 
NaOH 
+96.6cc. 
H2O 


3 cc. 
n/1 
H,P0 4 
+0.5 cc. 

n/1 
NaOH 
+96.5cc 
H2O 


3 cc. 
n/1 
H3PO4 
+0.6 cc. 

n/1 
NaOH 
+96.4cc. 
H 2 


3 cc. 
n/1 
H3PO4 
+0.7 cc. 

n/1 
NaOH 
+96.3cc 
H2O 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


20 
44 


69.32 
84.68 
CD 


62.85 
75.11 

(2) 


58.65 
70.60 
(3) 


58.45 
69.90 
(4) 


46.60 
58.17 
(5) 


43.00 
54.16 
(6) 


31.00 
42.20 
(7) 


22.31 
33.87 
(8), 


Dry wt. of 
gelatin disc. 


0.367 


0.367 


0.367 


0.370 


0.370 


0.370 


0.371 


0.374 


Solution 


3 cc. 
n/1 
H3PO4 
+0.8 cc. 

n/1 
NaOH 
+96.2cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+0.9 cc. 

n/1 
NaOH 
+96.1cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+1.0 cc. 

n/1 
NaOH 
+96.0cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+1.1 cc. 

n/1 
NaOH 
+95.9cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+1.2 cc. 

n/1 
NaOH 
+95.8cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+1.3 cc. 

n/1 
NaOH 
+95.7cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+1.4 cc. 

n/1 
NaOH 
+95.6cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+1.5 cc. 

n/1 
NaOH 
+95.5cc. 
H2O 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


20 
44 


15.30 
24.32 
(9) 


8.31 
11.28 
(10) 


7.10 
8.27 
(11) 


8.03 
9.41 
(12) 


8.68 
10.27 
(13) 


8.74 
10.44 
(14) 


9.35 
11.16 
(15) 


9.60 
11.56 
(16) 


Dry wt. of 
gelatin disc. 


0.380 


0.382 


0.383 


0.384 


0.386 


0.385 


0.388 


0.388 


Solution 


3 cc. 
n/1 
H3PO4 
+1.6 cc. 

n/1 
NaOH 
+95.4cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+1.7 cc. 

n/1 
NaOH 
+95.3cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+1.8 cc. 

n/1 
NaOH 
+95.2cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+1.9 cc. 

n/1 
NaOH 
+95.1cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+2.0 cc. 

n/1 
NaOH 
+95.0CC. 
H2O 


3 cc. 
n/1 
H3PO4 
+2.1 cc. 

n/1 
NaOH 
+94.9cc. 
H 2 


3 cc. 
n/1 
H3PO4 
+2.2 cc. 

n/1 
NaOH 
+94.8cc. 
H 2 


3 cc. 
n/1 
H3PO4 
+2.3 cc. 

n/1 
NaOH 
+94.7cc. 
H2O 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


20 
44 


9.49 
11.31 
(17) 


9.81 
11.60 
(18) 


9.81 
11.57 
(19) 


10.00 
11.90 

(20) 


10.23 
12.14 
(21) 


10.26 
12.40 

(22) 


10.80 
12.61 

(23) 


11.28 
13.12 
(24) 



584 



(EDEMA AND NEPHRITIS 
TABLE CXII— Concluded 



Dry wt. of 
gelatin, disc. 


0. 388 


0. 388 


0. 389 


0. 391 


391 


0. 392 


0. 394 


0. 394 


Solution 


3 cc. 
n/1 
H3PO4 
+2.4 cc. 

n/1 
XaOH 
+94.6cc. 
H 2 


3 cc. 
n/1 
H.3PO4 
+2.5 cc. 

n/1 
NaOH 
+94.5cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+2.6 cc. 

n/1 
NaOH 
+94.4cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+2.7 cc. 

1/n 
NaOH 
+94.3cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+2.8 cc. 

*/l 
NaOH 
+94.2cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+2.9 cc. 

n/1 
NaOH 
+94.1cc. 
H2O 


3 cc. 
n/1 
H3PO4 
+3.0 cc. 

n/1 
NaOH 
+94 cc. 
H2O 


100 cc. 
H2O 


Hrs. in the 
solution. 


Gain in parts of one pert of gelatin. 


20 
44 


11.52 
13.00 

(25) 


i 

13.14 j 15.81 
14.24 j 16.25 
(26) j (27) 


15.57 
16.17 

(28) 


17.71 
18.03 
(29) 


19.40 
19.37 
(30) 


19.91 
20.50 
(31) 


7.45 
8.80 
(H 2 0) 



35 



ao 



20 



15 



Gelafin 

Sodium Hydroxide- Phosphoric Acid 




Hours 



80lution No.5 



10 



15 



20 



30 



Figure 176. 



NEPHRITIS 585 
TABLE CXIII 



Gelatin — Sodium hydroxid with decreasing amounts of phosphoric acid 



Dry wt. of 
gelatin disc. 


0.347 


0.346 


0.343 


0.342 


0.341 


0.341 


0.340 


0.340 


Solution 


3 cc. 
n/l 
NaOH 
+3.0 cc. 

n/l 
H3PO4 
+94 cc. 
H2O 


3 cc. 
n/l 
NaOH 
+2.9 cc. 

n/l 
H3PO4 
+94.1 cc. 
H2O 


3 cc. 
n/l 
NaOH 
+2.8 cc. 
n/l 
H3PO4 
+94.2cc. 
H2O 


3 cc. 
n/l 
NaOH 
+2.7 cc. 

n/l 
H3PO4 
+94.3cc. 
H2O 


3 cc. 
n/l 
NaOH 
+2.6 cc. 

n/l 
H3PO4 
+94.4cc. 
H 2 


3 cc. 
n/l 
NaOH 
+2.5 cc. 

n/l 
H3PO4 
+94.5cc. 
H2O 


3 cc. 
n/l 
NaOH 
+2.4 cc. 

n/l 
H3PO4 
+94.6 cc. 
H2O 


3 cc. 
n/l 
NaOH 
+2.3 cc. 
n/l 
H3PO4 
+94.7cc. 
H2O 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


20 
44 


16.46 
17.00 
(1) 


16.40 
16.69 
(2) 


17.17 
18.02 

(3) 


17.55 
18.30 

(4) 


18.32 
18.82 

(5) 


18.36 
18.80 

(6) 


18.70 
19.53 
( 7) 


18.85 
20.53 
(8) 


Dry wt. of 
gelatin disc. 


0.340 


0.339 


0.338 


0.338 


0.338 


0.338 


0.337 


0.336 


Solution 


3 cc. 
n/l 
NaOH 
+2.2 cc. 

n/l 
H 3 P04 
+ 94.8cc. 
H2O 


3 cc. 
n/l 
NaOH 
+2.1 cc. 

n/l 
H3PO4 
+94.9cc. 
H2O 


3 cc. 
n/l 
NaOH 
+2.0 cc. 

n/l 
HaP0 4 
+95 cc. 
H2O 


3 cc. 
n/l 
NaOH 
+1.9 cc. 

n/l 
H3PO4 
+95.1cc. 
H2O 


3 cc. 
n/l 
NaOH 
+1.8 cc. 
n/l 
H3PO4 
+95.2cc. 
H2O 


3 cc. 
n/l 
NaOH 
+ 1.7 cc. 
n/l 
H3PO4 
+95.3cc. 
H2O 


3 cc. 
n/l 
NaOH 
+1.6 cc. 
n/l 
H3PO4 
+95.4cc. 
H2O 


3 cc. 
n/l 
NaOH 
+1.5 cc. 
n/l 
H3PO4 
+95.5cc. 
H2O 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


20 
44 


19.00 
"21.60 

(9) 


19.15 
22.42 
(10) 


19.65 
22.43 
(11) 


19.47 
21.65 
(12) 


20.25 
23.76 
(13) 


20.03 
23.55 
(14) 


20.45 
24.37 
(15) 


20.35 
24.70 
(16) 


Dry wt. of 
gelatin disc. 


0.336 


0.336 


0.335 


0.335 


0.334 


0.332 


0.331 


0.331 


Solution 


3 cc. 
n/l 
NaOH 
+1.4 cc. 
n/l 
H3PO4 
+95.6cc. 
H2O 


3 cc. 
n/l 
NaOH 
+1.3 cc. 
n/l 
H3PO4 
+95.7cc. 
H2O 


3 cc. 
n/l 
NaOH 
+1.2 cc. 
n/l 
H3PO, 
+95.8cc. 
H2O 


3 cc. 
n/l 
NaOH 
+1.1 cc. 
n/l 
H3PO4 
+95.9cc. 
H2O 


3 cc. 
n/l 
NaOH 
+1.0 cc. 

n/l 
H3PO4 
+96 cc. 
H2O 


3 cc. 
n/l 
NaOH 
+0.9 cc. 

n/l 
H3PO4 
+96.1cc. 
H2O 


3 cc. 
n/l 
NaOH 
+0.8 cc. 

n/l 
H3PO4 
+96.2cc. 
H2O 


3 cc. 
n/l 
NaOH 
+0.7 cc. 

n/l 
H3PO4 
+96.3cc. 
H2O 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


20 
44 


20.77 
25.55 
(17) 


21.05 
26.00 
(18) 


21.30 
25.85 
(19) 


20.97 
25.58 
(20) 


22.06 
28.14 
(21) 


22.04 
28.50 
(22) 


21.85 
28.31 
(23) 


22.21 
29.03 
(24) 



586 



(EDEMA AND NEPHRITIS 
TABLE CXIII— Concluded 



Dry wt. of 
gelatin disc. 


0. 330 


330 


0. 330 


0. 329 


0. 329 


0. 328 


0. 327 


V . Oil 


Solution 


3 cc. 
n/1 
NaOH 
+ 0.6 cc. 

n/1 
H3PO4 
+ 96.4cc. 
H2O 


3 cc. 
n/1 
NaOH 
+ 0.5 cc. 

n/1 
H3PO4 
+ 96.5cc. 
H 2 


3 cc. 
n/1 
NaOH 
+ 0.4 cc. 

n/1 
H3PO4 
+ 96.6cc. 
H2O 


3 cc. 
n/1 
NaOH 
+ 0.3 cc. 

n/1 
H3PO4 
+ 96.7cc. 
H2O 


3 cc. 
n/1 
NaOH 
+ 0.2 cc. 

n/1 
H3PO4 
+ 96.8cc. 
H2O 


3 cc. 
n/1 
NaOH 
+ 0.1 cc. 

n/1 
H 3 PO. 
+ 96.9cc. 
H2O 


3 cc. 
n/1 
NaOH 
+ 97 cc. 
H 2 


100 cc. 
H 2 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


20 
44 


23.56 
31.80 
(25) 


22.70 
30.81 
(26) 


23.48 
32.66 
(27) 


22.13 
31.26 
(28) 


24.51 
35.68 
(29) 


24.73 
35.61 
(30) 


24.00 
34.64 
(31) 


6.94 
8.33 
(H2Q) 



The water absorption curve falls as the neutralization progresses, 
until a low point is attained in the theoretically pure solution 
of trisodium phosphate. 

TABLE CXIV 

Gelatin — Monosodium citrate 



Dry weight of 
gelatin disc. 


0.370 


0.373 


0.373 


0.373 


0.370 


Solution 


5 cc. m/1 
monosodium 
citrate 
+ 95 cc. 
H2O 


15 cc. m/1 
monosodium 
citrate 
+ 85 cc. 
H 2 


25 cc. m/1 
monosodium 
citrate 
+ 75 cc. 
H2O 


50 cc. m/1 
monosodium 
citrate 
+ 50 cc. 
H 2 


100 cc. 
H 2 


Hours in the 
solution. 


Gain in parts of one part gelatin. 


18 
24 
41 
48 
66 
71 
91 


7.17 
7.91 
8.69 
8.92 
9.30 
9.35 
9.51 
(I) 


6.74 
7.47 
8.16 
8.44 ~~ 
8.81 
8.85 
8.88 
(ID 


6.20 
7.11 
. 8.27 
8.59 
9.08 
9.12 
9.41 
(HI) 


6.23 
7.12 
8.01 
8.40 
9.00 
9.11 
9.28 
(IV) 


5.52 
5.94 
6.35 
6 52 
6.84 
6.90 
7.27 
(HjO) 



§2 

We studied next the effects of citric acid and the citrates upon the 
swelling of gelatin. The citrate solutions were prepared by adding 



NEPHRITIS 587 
TABLE CXV 



Gelatin — Disodium citrate 



Dry weight of 
gelatin disc. 


0.365 


0.367 


0.369 


0.369 


0.365 


Solution 


5 cc. m/1 
disodium 
citrate 
+95 cc. 
H 2 


15 cc. m/1 
disodium 
citrate 
+85 cc. 
H2O 


25 cc. m/1 
disodium 
citrate 
+75 cc. 
H2O 


50 cc. m/1 
disodium 
citrate 
+50 cc. 
H2O 


100 cc. 
H2O 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


1 Q 
IS 

24 
41 
48 
66 
71 
91 


6.39 
6.88 
7.34 
7.77 
7.70 
7.76 
7.82 
(I) 


6.38 
6.92 
7.41 
7.58 
7.83 
7.84 
7.95 
(ID 


5.11 
6.44 
7.26 
7.49 
7.74 
7.71 
7.89 
(HI) 


5.12 
5.78 
6.24 
6.48 
6.74 
6.77 
7.86 
(IV) 


5.47 
5.92 
6.31 
6.49 
6.89 
6.96 
7.37 
(H2O) 






TABLE CXVI 








Gelatin — Trisodium citrate 






Dry weight of 
gelatin disc. 


0.363 


0.363 


0.363 


0.364 


0.363 


Solution 


5 cc. m/1 
trisodium 
citrate 
+95 cc. 
H2O 


15 cc. m/1 
trisodium 
citrate 
+ 85 cc. 
H2O 


25 cc. m/1 
trisodium 
citrate 
+75 cc. 
H2O 


50 cc. m/1 
trisodium 
citrate 
+50 cc. 
H2O 


100 cc. 
H2O 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


18 
24 
41 
48 
66 
71 
91 


7.12 
7.75 
8.23 
8.50 
8.73 
8.73 
8.81 

m 


6.42 
7.01 
7.51 
7.69 
7.95 
7.96 
8.06 
(ID 


5.51 
6.04 
6.51 
6.68 
6.93 
6.96 
7.04 
(HI) 


3.12 
3.52 
3.90 
4.02 
4.21 
4.23 
4.30 
(IV) 


5.53 
5.98 
6.35 
6.58 
6.99 
7.08 
7.62 
(H2O) 



to each other the theoretically necessary amounts of carefully 
standardized citric acid and sodium hydroxid solutions. 

In Figs. 177, 178 and 179, which portray graphically the 
experimental findings contained in Tables CXIV, CXV and CXVI, 
are shown the effects, respectively, of mono-, di- and trisodium 



588 



(EDEMA AND NEPHRITIS 



citrate in different eoncentrations upon the swelling of gelatin. 
As evident in Fig. 177,monosodium citrate in all the concentrations 




used increases the amount of water absorbed by gelatin over and 
above the amount absorbed in pure water. The same is true of 
the lower concentrations of equimolar solutions of disodium 



NEPHRITIS 



589 



citrate. For both of these salts there is a progressive decrease in 
swelling with increase in the concentration of the salt. As evident 




in the lowermost curve of Fig. 178, a sufficiently high concentra- 
tion of disodium citrate makes gelatin swell even less than in pure 
water. The effects of trisodium citrate are shown in Fig. 179. 



590 



(EDEMA AND NEPHRITIS 



Low concentrations of this salt also increase the amount of water 
absorption over the amount absorbed in pure water, but with 




increasing concentration there is less and less swelling, until the 
amounts of water absorbed in the higher concentrations of the 
trisodium citrate are distinctly less than in pure water. 



NEPHRITIS 



591 



Having determined in this fashion the effects of different con- 
centrations of the different citrates, we investigated the swelling 
of gelatin in citrate mixtures varying from the extreme on the one 
side of pure citric acid through equimolar concentrations of mono-, 
di- and trisodium citrate to pure sodium hydroxid on the other. 
The results as shown in Fig. 180 and Table CXVII are self-explan- 

TABLE CXVII_ 



Gelatin — Citric acid, through citrates, to sodium hydroxid 



Dry weight of 
gelatin disc. 


0.332 


0.334 


0.335 


0.335 


0.336 


0.338 


0.339 


Solution 


10 cc. 
n/1 
citric 
acid 
+ 90 cc. 
H 2 


8 cc. 
n/1 
citric 
acid 
+ 2 cc. 

m/1 
mono- 
sodium 
citrate 
+ 90 cc. 
H 2 


6 cc. 
n/1 
citric 
acid 
+ 4 cc. 

m/1 
mono- 
sodium 
citrate 
. +90 cc. 
H2O 


4 cc. 
n/1 
citric 
acid 
+ 6 cc. 

m/1 
mono- 
sodium 
citrate 
+ 90 cc. 
H2O 


2 cc. 
n/1 
citric 
acid 
+ 8 cc. 
m/1 
mono- 
sodium 
citrate 
+ 90 cc. 
H2O 


10 cc. 

m/1 
mono- 
sodium 
citrate 
+ 90 cc. 

H2O 


8 cc. 

m/1 
mono- 
sodium 
citrate 
+ 2 cc. 

m/1 
disodium 
citrate 
+90 cc. 

H2O 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


24 
48 
72 


46.10 
51.08 
60.70 
(1) 


27.58 
33.14 
36.72 
(2) 


18.29 
22.71 
25.10 

(3) 


14.11 : 
17.04 
18.53 
(4) 


11.08 
13.09 
14.18 

(5) 


9.02 
10.40 
11.16 

(6) 


7 66 
8.84 
9.47 
(7) 


Dry weight of 
gelatin disc. 


0.340 


0.341 


0.341 


0.342 


0.342 


0.345 


0.345 


Solution 


6 cc. 

m/1 
mono- 
sodium 
citrate 
+ 4 cc. 

m/1 
disodium 
citrate 
+ 90 cc. 

H 2 


4 cc. 

m/1 
mono- 
sodium 
citrate 
+ 6 cc. 

m/1 
disodium 
citrate 
+ 90 cc. 

H2O 


2 cc. 

m/1 
mono- 
sodium 
citrate 
+ 8 cc. 

m/1 
disodium 
citrate 
+ 90 cc. 

H2O 


10 cc. 
m/1 
di- 
sodium 
citrate 
+ 90 cc. 
H2O 


8 cc. 

m/1 

di- 
sodium 
citrate 
+ 2 cc. 

m/1 
trisodium 
citrate 
+ 90 cc. 

H2O 


6 cc. 

m/1 
di- 
sodium 
citrate 
+ 4 cc. 

m/1 
trisodium 
citrate 
+ 90 cc. 

H2O 


4 cc. 

m/1 

di- 
sodium 
'citrate 
+ 6 cc. 

m/1 
trisodium 
citrate 
+ 90 cc. 

H2O 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


24 
48 
72 


7.60 
8.61 
9.27 

(8) 


7.50 
8.45 
9.00 
(9) 


7.55 
8.44 
9.08 
(10) 


8.02 
8.93 
9.46 
(11) 


8.05 
8.96 
9.50 
(12) 


8.22 
8.80. 
9.48 
(13) 


8.26 
9.23 
10.02 
(14) 



592 (EDEMA AND NEPHRITIS 



TABLE CXVII— Concluded 



Dry wt. of 
gelatin disc. 


0.346 


0.350 


0.351 


0.352 


0.352 


0.353 


0.353 


0.350 


Solution 


m/1 
disodium 
citrate 
+ 8 cc. 
m/1 
trisodium 
citrate 
+ 90 cc. 
H 2 


m/1 
trisodium 
citrate 
+ 90 cc. 

H2O 


8 cc 
m/1 
trisodium 
citrate 
+ 2 cc. 

n/1 
NaOH 
+ 90 cc. 
H2O 


6 cc 

m/1 
trisodium 
citrate 
+ 4 cc. 

n/1 
NaOH 
+90 cc. 

H2O 


m/1 
trisodium 
citrate 
+ 6 cc. 

n/1 
NaOH 
+ 90 cc. 

H2O 


2 cc 

m/1 
trisodium 
citrate 
+ 8 cc. 

n/1 
NaOH 
+90 cc. 

H2O 


10 cc. 
n/1 
NaOH 
+90 cc. 
H2O 


1UU cc. 

H20 


Hrs. in the 
solution. 


Gain in parts of one part of gelatin. 


24 
48 
72 


8.19 
9.34 
9.54 
(15) 


8.16 
9.03 
9.41 

(16) 


10.51 
12.90 
15.06 
(17) 


14.22 
20.54 
28.83+ 
(18) 


17.01 

27.83+ 

dis- 
solving 
(19) 


24.22+ 

dis- 
solving 

(20) 


dis- 
solving 

dis- 
solved 

(21) 


6.35 
7.12 
8.11 
H2O 



atory. The three curves show the amounts of water absorbed at 
the end of 24, 48 and 72 hours. As readily evident, most swelling 
occurs in the pure citric acid, and less and less swelling as the pure 
citric acid gives way to the monosodium citrate. Between mono- 
sodium citrate, disodium citrate and trisodium citrate there is little 
change in the amount of water absorbed, this portion of the 
curve describing a gentle arc. As the excess of alkali appears in 
the mixture, the curve again ascends steeply. 

§ 3 

The swelling of -gelatin in carbonate mixtures has also been 
given some study. The results here again confirm the general 
conclusions previously cited for phosphates and citrates. In the 
carbonate series we began with pure sodium bicarbonate and 
gradually replaced this by molecularly equivalent amounts of 
sodium carbonate, and this in turn by sodium hydroxid. The 
effects upon the swelling of gelatin as we pass from the sodium 
bicarbonate through the sodium carbonate to sodium hydroxid is 
shown in Fig. 181 and Table CXVIII. The curves show the 
amounts of swelling at the end of 5 J, 29 and 53 hours. As is 
clearly apparent, gelatin swells more in a solution of sodium 



NEPHRITIS 




(EDEMA AXD NEPHRITIS 



TABLE CXYIII 



Gelatin — Sodium bicarbonate, to sodium carbonate, to sodium hydroxid 



E : v ■? _ ; : 

geLarir: lis:. 




0. 369 


0.370 


0.370 


0.371 


0.371 


0.372 


Sedation 


3 cc 
m 1 
XaHCCh 


1.9 cc. 

m 1 
XaHCCh 
4-0.1 cc. 

m 1 
Xa.-CCh 
— 9S cc. 


1.8 ec. 
m 1 
XaHCCh 
-f 0.2 cc. 

m 1 
NaaOOb 
— 9b cc. 


1.7 cc. 

m 1 
NaHOOb 
- 0.3 cc. 

m/1 
XaHCCh 
+ 9S ec. 

H=0 


1.6 cc. 
m 1 
XaHCCh 

-j- 0.4 ec. 

m 1 
Xa:CCh 
— 9S cc. 
H-O 


1.5 cc. 

m 1 
XaHCCh 
+ 0.5 ce. 

ml 
Xa : CCh 
— 98 ec. 

HsO 


1.4 cc. 

m 1 
XaHCCh 
4- 0.6 ec. 

m 1 
Xa;CCh 
-9S ce. 

HrO 


E:urs iu 

solution. 




Ga 






5.5 
29 
53 


5. IS 
11.52 
13.05 


5.30 
11. S4 
13.40 


5.65 
12.07 
13.51 

(3) 


6.00 
12.56 
14.00 


5.66 
11.91 
13.30 


5. 5S 
12.00 
13.33 


5.97 
12.35 
13.75 


Drv ~ ~ : 
zk^ir. dis:. 


0.372 


0.373 




0.376 


0. 377 


0.377 


0.379 




1.3 cc. 
ml 
NaHOOb 

— 0.7 cc. 
ml 

XaiCOs 

— b* > " _ . 

TT_/"i 

JZLI '_' 
1 


m 1 
NaHOOb 
-r 0.8 cc. 

m 1 
Xa.-CCh 
— 9S cc. 

IT M 1 


m 1 
XaHCCh 
-f 0.9 cc. 

m 1 

x^-ca 


m 1 
XaECC: 
+ 1.0 cc. 

m 1 
Xa:CO: 


m 1 
XaHCCh 
-h 1.1 cc. 

m 1 
XarCCh 


O.S ec. 

m 1 
XaHCO: 
+ 1.2 cc. 

m 1 
XaHCCh 

HjO 


0.7 ec. 

m 1 
XaHCCh 
— 1.3 cc. 

m 1 
XaKTOi 
— 9S cc. 

H-O 


Hours ir. the 






on in parts 




5.5 
29 
53 


11.90 
13.41 
(8) 


12.20 
13.47 

(9) 


12.22 
13.60 
(10) 


12.06 
13.55 
(11) 




12.16 
13.63 
(13) 


6.00 
12.11 
13.50 

(14) 


Dry weight of 
gelatin disc. 


0.379 


0.379 


0.380 


0.3S0 




- 


0.382 


Solution 


0.6 cc. 
m 1 
NaHOOb 
■f 1.4 cc. 

ml 
XasCOs 
— 9S ec. 
tt r\ 

tl3\J 


0.5 cc. 
m 1 
XaHCCh 
-r 1-5 cc. 

m 1 
XajCCh 


0.4 cc. 
m 1 

>" : : 

Hh 1.6 cc. 

ra 1 
XaiCCh 
— 9S cc. 


0.3 cc. 
m/1 
XaHCO: 

— 1.7 cc. 
m 1 

Xa-CCh 

— 9S cc. 




0.1 cc. 
ni 1 
XaHCCh 
+ 1.9 cc. 


2.0 ec. 

m 1 
Xa^TCh 
-95 cc. 

HrO 


Honrs in the 




Ga 




of one part of gelatin. 


5.5 
29 
53 


6.50 
12.60 
14.01 

(15) 


6.30 
12.00 
13.27 

(16) 


6.50 
12.13 
13.3-5 

(17) 


6.34 
12.16 
13.52 

(18) 


6.10 
12.21 
13.60 

(19) 


6.51 
12.00 
13.14 

(20) 


6.35 
12.35 
13.50 

(21) 



NEPHRITIS 



595 



TABLE CXVIII— Concluded 



Dry weight of 
gelatin disc. 


0.382 


0.382 


0.384 


0.384 


0.385 


0.387 


0.388 


Solution 


1.9 cc. 
m/1 
Na 2 C0 3 
+ 0.1 cc. 

n/1 
NaOH 
+ 98 cc. 
H 2 


1.8 cc. 
m/1 
Na 2 C0 3 
+ 0.2 cc. 
n/1 
NaOH 
+ 98 cc. 
H2O 


1.7 cc. 
m/1 
Na 2 C0 3 
+ 0.3 cc. 
n/1 
NaOH 
+ 98 cc. 
H2O 


1.6 cc. 
m/1 
Na 2 C0 3 
+ 0.4 cc. 
n/1 
NaOH 
+ 98 cc. 
H 2 


1.5 cc. 
m/1 
Na 2 C0 3 
+ 0.5 cc. 
n/1 
NaOH 
+ 98 cc. 
H 2 


1.4 cc. 
m/1 
Na 2 C0 3 
+ 0.6 cc. 
n/1 
NaOH 
+ 98 cc. 
H2O 


1.3 cc. 
m/1 
Na 2 C0 3 
+ 0.7 cc. 
n/1 
NaOH 
+ 98 cc. 
H2O 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


5.5 
29 
53 


6.92 
13.01 
14.26 

(22) 


7.21 
13.28 
14.42 

(23) 


7.45 
13.09 
14.24 

(24) 


7.40 
13.78 
15.02 

(25) 


8.20 
14.65 
15.63 

(26) 


8.78 
15.20 
16.13 

(27) 


9.80 
16.34 
17.24 

(28) 


Dry weight of 
gelatin disc. 


0.390 


0.390 


0.390 


0.392 


0.393 


0.393 


0.395 


Solution 


1.2 cc. 
m/1 
Na 2 C0 3 
+ 0.8 cc. 
n/1 
NaOH 
+ 98 cc. 
H 2 


1.1 cc. 
m/1 
Na 2 C0 3 
+ 0.9 cc. 
n/1 
NaOH 
+ 98 cc. 
H 2 


1.0 cc. 
m/1 
Na 2 COs 
+ 1.0 cc. 
n/1 
NaOH 
+ 98 cc. 
H2O 


0.9 cc. 
m/1 
Na 2 C0 3 
+ 1.1 cc. 
n/1 
NaOH 
+ 98 cc. 
H 2 


0.8 cc. 
m/1 
Na 2 C0 3 
+ 1.2 cc. 
n/1 
NaOH 
+ 98 cc. 
H 2 


0.7 cc. 
m/1 
Na 2 C0 3 
+ 1.3 cc. 
n/1 
NaOH 
+ 98 cc. 
H2O 


0.6 cc. 
m/1 
Na 2 C0 3 
+ 1.4 cc. 
n/1 
NaOH 
+ 98 cc. 
H 2 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


5.5 
29 
53 


9.58 
16.34 
17.28 
n (29) 


9.93 
17.51 
18.51 

(30) 


10.18 
17.55 
18.76 
(31) 


10.14 
17.51 
18.13 
(32) 


11.85 
19.84 
20.45 
(33) 


11.70 
20.32 
21.94 
(34) 


11.40 
20.10 
21.76 

(35) 


Dry weight of 
gelatin disc. 


0.395 


0.396 


0.396 


0.396 


0.397 


0.397 


0.368 


Solution 


0.5 cc. 
m/1 
Na 2 C0 3 
+ 1.5 cc. 
n/1 
NaOH 
+ 98 cc. 
H2O 


0.4 cc. 
m/1 
Na 2 C0 3 
+ 1.6 cc. 

n/1 
. NaOH 
+ 98 cc. 
H2O 


0.3 cc. 
m/1 
Na 2 C0 3 
+ 1.7 cc. 
n/1 
NaOH 
+ 98 cc. 
H2O 


0.2 cc. 
m/1 
Na 2 C0 3 
+ 1.8 cc. 
n/1 
NaOH 
+ 98 cc. 
H 2 


0.1 cc. 
m/1 
Na 2 COs 
+ 1.9 cc. 

n/1 
NaOH 
+ 98 cc. 
H 2 


2.0 cc. 

n/1 
NaOH 
+ 98 cc. 
H2O 


100 cc. 
H 2 


Hours in the 
solution. 


Gain in parts of one part of gelatin. 


5.5 
29 
53 


11.86 
20.64 
22.50 
(36) 


11.97 
20.73 
22.67 
(37) 


11.77 
20.71 
22.24 
(38) 


11.75 
21.72 
24.90 
(39) 


11.76 
22.45 
25.05 
(40) 


13.12 
24.00 
29.00 
(41) 


3.36 
6.23 
7.18 
(H 2 0) 



596 



(EDEMA AND NEPHRITIS 



bicarbonate than in pure water and the amount of this swelling 
increases progressively as we pass from the sodium bicarbonate 




to sodium carbonate and then more abruptly as we enter the realm 
of the purer sodium hydroxid. 

2. On the Liquefaction or " Solution " of Gelatin in Polybasic 
Acids and their Salts 

Since our previous experiments 1 on the liquefaction or "solu- 
tion" of gelatin in acids or alkalies with or without the simulta- 

1 Mabtin H. Fischer: Science, 42, 223 (1915); Kolloid-Zeitschr., 17, 1 
(1915); also see pages 508 and 518; Martin H. Fischer and Marian O. 
Hooker: Science, 46, 189 (1917.) 



NEPHRITIS 



597 



neous presence of various neutral salts might have voiced against 
them the same criticisms which have been raised against our 
experiments on swelling, namely, that the effects of the acids 
and alkalies were not tried out in the presence of " buffer " 
salts and so could not be applied to the living organism, we 
ran experiments on the solution of gelatin in parallel with those 
just described on the swelling of gelatin in various poly basic 
acids and their salts. 1 As the following experimental facts 
show, there is a progressive increase in the tendency of gelatin 
to go into " solution " in mixtures of the salts of polybasic acids as 
the amount of acid or alkali in these mixtures is increased from a 
given low point. 

The same gelatin was used in these experiments as was 
employed in our previous ones. Its quality was of such high grade 
that an 0.8 per cent solution of the stock gelatin would set into a 
solid mass when left to itself for a few hours at 25° C. To make 
sure of a stiff gelatin mixture we used a concentration well above 
this, namely, 1 per cent gelatin and set the thermostat for 20° C. 
It should be added that all the tubes and their contents were 
treated in exactly the same fashion as to methods of mixing, 
exposure to heat or other influences which might change tem- 
porarily their gelation characteristics, etc. 

In Table CXIX are shown the effects of a progressive change 
from the extreme of a pure phosphoric acid through equimolar 
concentrations of mono-, di- and trisodium phosphate to pure 
sodium hydroxid upon the physical state of a fixed amount of 
gelatin contained in a unit volume of solvent. The maintenance 
of solidity by the gelatin in the middle of the series with progressive 
increase in fluidity to the left or to the right of this middle point 
can be more easily observed in the actual experiments than can be 
described in words or shown in such a photograph as that of Fig. 
182. From so stiff a gelatin that it vibrates when the tube is 
touched in the middle of the series, we pass through gelatins on 
either side of this which show the first evidences of a tendency to 
flow, to the end members which are almost as fluid as thin soup. 
The change from the solid to the fluid state may be observed in 
Fig. 182 by noting the line of the meniscus in the tubes; while on 
slanting the tubes this remains fixed and therefore forms an angle 

1 Martin H. Fischer and Ward D. Coffman: Science, 46, 189 (1917); 
Jour. Am. Chem. Soc, 40, 303 (1918). 



598 



(EDEMA AND NEPHRITIS 



TABLE CXIX 

Gelatin — Phosphoric acid through phosphates to sodium hydroxid 



Concentration of solution. 



(1) 
. (2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 

(9) 

(10) 

(11) 

(12) 
(13) 

(14) 

(15) 

(16) 

(17) 
(18) 
(19) 
(20) 
(21) 
(22) 



5 cc. 2% 
5 cc. 2 % 
5 cc. 2% 
5 cc. 2 % 
5 cc. 2% 
5 cc. 2 % 
5 cc. 2% 
5 cc. 2% 

H 2 
5 cc. 2% 

H2O 



o cc. 



2% 



B.2O 
5 cc. 2 % 

H 2 
5 cc. 2% 
5 cc. 2% 

H2O 
5 cc. 2% 

H2O 
5 cc. 2% 

H2O 
5 cc. 2% 

H2O 
5 cc. 2% 
5 cc. 2% 
5 cc. 2% 
5 cc. 2% 
5 cc. 2% 
5 cc. 2% 



gelatin +5.0 cc. H2O (control) 

gelatin +1.0 cc. n/1 H3PO4+4.O cc. H 2 

gelatin +0.8 cc. n/1 H3PO4+O.2 cc.m/1 NaH 2 P0 4 +4cc. H 2 
gelatin +0.6 cc. n/1 H3PO4+O.4 cc.m/1 NaH 2 P0 4 +4cc. H2O 
gelatin +0.4 cc. n/1 H3PO4+O.6 cc. m/1 NaH 2 P0 4 +4cc. H 2 
gelatin +0.2 cc. n/1 H3PO4+O.8 cc. m/1 NaH 2 P0 4 +4 cc. H2O 
gelatin +1.0 cc. m/1 NaH 2 PO4+4.0 cc. H2O 
gelatin +0.8 cc. m/1 NaH 2 PO 4 + 0.2 cc. m/1 Na2HP0 4 + 4 cc. 

gelatin + 0.6 cc. m/1 NaH 2 P04 + 0.4 cc. m/1 Na 2 HP04 + 4 cc. 

gelatin + 0.4 cc. m/1 NaH 2 PO4 + 0.6 cc. m/1 Na 2 HP04 + 4 cc. 

gelatin + 0.2 cc. m/1 NaH 2 P04 + 0.8 cc. m/1 Na 2 HPC>4 + 4 cc. 

gelatin +1.0 cc. m/1 Na 2 HPO4+4.0 cc. H 2 

gelatin + 0.8 cc. m/1 Na 2 HPC>4+0.2 cc. m/1 NasP04 + 4 cc. 

gelatin + 0.6 cc. m/1 Na : HP04 + 0.4 cc. m/1 Na 3 P0 4 + 4 cc. 

gelatin + 0.4 cc. m/1 Na 2 HP04 + 0.6 cc. m/1 Na 3 P04+ 4 cc. 

gelatin + 0.2 cc. m/1 Na 2 HP04+ 0.8 cc. m/1 NasP04+ 4 cc. 

gelatin + 0.1 cc. m/1 Na 3 P04 + 4.0 cc. H 2 
gelatin + 0.8 cc. m/1 Na 3 P04+ 0.2 cc. n/1 NaOH + 4 cc. H 2 
gelatin + 0.6 cc. m/1 Na 3 PO4 + 0.4 cc. n/1 NaOH +4 cc. H2O 
gelatin + 0.4 cc. m/1 Na 3 PO4 + 0.6 cc. n/1 NaOH + 4 cc. H2O 
gelatin + 0.2 cc. m/1 Na 3 PO4 + 0.8 cc. n/1 NaOH +4 cc. H 2 
gelatin + 1.0 cc. n/1 NaOH + 4 cc. H2O 



with the horizontal in the middle of the series, it assumes a hori- 
zontal position as we approach either end. 

Since the concentration of the phosphate in Table CXIX is 
about ten times that observed, for instance, in the tissues of the 
human body, we did a second series at a lower concentration of the 
phosphate and at one more nearly corresponding to physiological 
conditions. The results so far as maintenance of solidity or lique- 
faction of the gelatin is concerned are, however, as shown in 
Table CXX, identical with those previously described in connec- 
tion with Table CXIX. 

As an example of another polybasic acid commonly found in 
living protoplasm, we chose citric acid, studying its effects by 
noting the results incident to progressive change from citric acid 
through mono-, di- and trisodium citrate in equimolar concentra- 
tions to pure sodium hydroxid. As shown in Table CXXI and 
Fig. 183, gelatin again remains solid in the middle of such a series 



NEPHRITIS 



599 





and tends to liquefy as we pass toward the acid or alkaline 
extreme. 

In Table CXXII and Fig. 184 are shown the effects of pro- 



NEPHRITIS 



601 



TABLE CXX 



Gelatin — Phosphoric acid through phosphates to sodium hydroxid 





Concentration of solution. 


Physical 


(1) 5 cc. 2% gelatin +5.0 cc. H 2 (control) - 


solid 


(2) 


5 cc. 2% gelatin +0.10 cc. n/1 H 3 PO4+4.90 cc. H 2 


liquid 


(3) 5 cc. 2 % gelatin +0.08 cc. n/1 H3PO4 + 0.02 cc. m/1 NaH 2 P0 4 + 4.9 cc. 




H2O 


liauid 


(4) 


5 cc. 2% gelatin +0.06 cc. n/1 H3PO4 + 0.04 cc. m/1 NaH 2 P04 + 4.9 cc. 






H 2 


^ P TYi l - « rtl i rl 


(5) 5 cc. 2% gelatin +0.04 cc. n/1 H3PO4 + 0.06 cc. m/1 NaH 2 P04 + 4.9 cc. 






Xl2U 


S6. ini - solicl 


(6) 


5 cc. I % gelatin -f-D.OZ cc. n/1 ±i3JrU4 + U.Uo cc. m/1 JNa-n 2 F(j4 + 4.9 cc. 






XT r\ 
H2U 


solid 


(7) 


5 cc. z % gelatin -f- (J. 1 U cc. m/1 JNarL 2 Jr(J 4 + 4.9U cc. xi 2 <J 


solid 


Co) 


o cc. <z ye gelatin -^u.uo cc. m/ 1. in ari2-r U4 t-u.uz cc. m/ 1 in a2xi r U4 -(- 4.y 






CC. H2O 


solid 


(9) 


5 cc 2% gelatin +0.06 cc m/1 NaH 2 P0 4 40.04 cc. m/1 Na 2 HPC>4 + 4.9 






cc. H2O 


solid 


(10) 


5 cc. 2% gelatin +0.04 cc. m/1 NaH 2 P0 4 +0.06 cc. m/1 Na 2 HP0 4 + 4.9 






cc. H2O 


solid 


(11) 


5 cc. 2% gelatin +0.02 cc. m/1 NaH 2 P04 40.08 cc. m/1 Na 2 HP04 + 4.9 






cc. H 2 


solid 


(12) 


5 cc. 2% gelatin +0.10 cc. m/1 Na 2 HP0 4 +4.90 cc. H2O 


solid 


(13) 


5 cc. 2% gelatin +0.08 cc. m/l Na 2 HPO, +0.02 cc. m/1 Na 3 P0 4 + 4.9 






cc. H2O 




(14) 


5 cc. 2% gelatin +0.06 cc. m/1 Na 2 HPO4+0.04 cc. m/1 Na 3 P04+4.9 cc. 






H2O 


solid 


(15) 


5 cc.2% gelatin +0.04 cc. m/1 Na 2 HP04 +0.06 cc. m/1 Na 3 P0 4 +4.9 cc. 






H 2 


semi-solid 


(16) 


5 cc. 2% gelatin +0.02 cc. m/1 Na 2 HP04 +0.08 cc. m/1 Na 3 P0 4 +4.9 cc. 






H 2 


semi-solid 


(17) 


5 cc. 2% gelatin +0.10 cc. m/1 Na 3 PO 4 +4.90 cc. E 2 


semi-solid 


(18) 


5 cc. 2% gelatin +0.08 cc. m/1 NasPO4 + 0.02 cc. n/1 NaOH +4.9 cc. 






H 2 0~ 


liquid 


(19) 


5 cc. 2% gelatin +0.06 cc. m/1 Na 3 P04+ 0.04 cc. n/1 NaOH + 4.9 cc. 






H2O 


liquid 


(20) 


5 cc. 2% gelatin +0.04 cc. m/1 NasPO4+0.06 cc. n/1 NaOH + 4.9 cc. 






H 2 


liquid 


(21) 


5 cc. 2% gelatin +0.02 cc. m/1 Na 3 P04 + 0.08 cc. n/1 NaOH + 4.9 cc. 




H2O 


liquid 


(22) 


5 cc. 2% gelatin +0.10 cc. n/1 NaOH +4.9 cc. H2O 


liquid 



gressive change from sodium bicarbonate through sodium carbon- 
ate to sodium hydroxid. The carbonates in the concentrations 
indicated in this table showed a greater tendency to liquefy the 
gelatin than was observed in the phosphate or citrate mixtures 
previously discussed. To show the effects of the different salt 
mixtures this series of experiments was therefore kept at a some- 
what lower temperature, namely, 5° C. At this temperature the 
gelatin remains solid in the pure sodium bicarbonate but tends to 
liquefy as this is replaced by carbonate, or the carbonate by pure 
sodium hydroxid. 



602 



(EDEMA AND NEPHRITIS 



TABLE CXXI 
Gelatin — Citric acid through citrates to sodium hydroxid 



Concentration of solution. 



Physical 
state. 



(x) 5 cc. 2% gelatin +5.0 cc. H 2 (control) 

(1) 5 cc. 2% gelatin +1.0 cc. n/1 citric acid +4.0 cc H 2 

(2) 5 cc. 2% gelatin +0.8 cc. n/1 citric acid +0.8 cc. m/4 monosodium ci- 

trate +3.4 cc. H 2 

(3) 5 cc. 2% gelatin + 0.6 cc. n/1 citric acid + 1.6 cc. m/4 monosodium ci- 

trate +2.8 cc. H2O 

(4) 5 cc. 2% gelatin + 0.4 cc. n/1 citric acid + 2.4 cc. m/4 monosodium ci- 

trate +2.2 cc. H2O 

(5) 5 cc. 2 % gelatin + 0.2 cc. n/1 citric acid + 3.2 cc. m/4 monosodium ci- 

trate +1.6 cc. H2O 

(6) 5cc.2% gelatin + 4.0 cc. m/4 monosodium citrate +1.0 cc. H 2 

(7) 5 cc. 2% gelatin + 3.2 cc. m/4 monosodium citrate +0.8 cc. m/4 di- 

sodium citrate +1.0 cc. H 2 

(8) 5 cc. 2% gelatin + 2.4 cc. m/4 monosodium citrate +1.6 cc. m/4 di- 

sodium citrate +1.0 cc. H2O 

(9) 5 cc. 2% gelatin + 1.6 cc. m/4 monosodium citrate + 2.4 cc. m/4 di- 

sodium citrate +1.0 cc. H2O 

(10) 5 cc. 2% gelatin + 0.8 cc. m/4 monosodium citrate + 3.2 cc. m/4 di- 

sodium citrate +1.0 cc. H2O 

(11) 5 cc. 2% gelatin +4.0 cc. m/4 disodium citrate +1.0 cc. H 2 

(12) 5 cc. 2% gelatin +3.2 cc. m/4 disodium citrate +0.8 cc. m/4 trisodium 

citrate +1.0 cc H 2 

(13) 5 cc. 2% gelatin +2.4 cc. m/4 disodium citrate +1.6 cc. m/4 trisodium 

citrate +1.0 cc. H 2 

(14) 5 cc. 2% gelatin +1.6 cc. m/4 disodium citrate +2.4 cc. m/4 trisodium 

citrate +1.0 cc. H2O 

(15) 5 cc. 2% gelatin +0.8 cc. m/4 disodium citrate +3.2 cc. m/4 trisodium 

citrate +1.0 cc. E 2 

(16) 5 cc. 2% gelatin +4.0 cc. m/4 trisodium citrate +1.0 cc. H2O 

(17) 5 cc. 2% gelatin + 3.2 cc. m/4 trisodium citrate + 0.8 cc. n/1 NaOH 

+1.0 cc. H2O 

(18) 5 cc. 2% gelatin +2.4 cc. m/4 trisodium citrate + 1.6 cc. n/1 NaOH 

+1.0 cc. H2O 

(19) 5 cc. 2% gelatin +1.6 cc. m/4 trisodium citrate + 2.4 cc. n/1 NaOH 

+ 1.0 cc. H2O 

(20) 5 cc. 2% gelatin +0.8 cc. m/4 trisodium citrate +3.2 cc. n/1 NaOH 

+1.0 cc. H2O 

(21) 5 cc. 2% gelatin +4.0 cc. n/1 NaOH +1.0 cc. H 2 



solid 
li : uid 

semi-solid 

solid 

solid 

solid 
solid 

solid 

solid 

solid 

solid 
solid 

solid 

solid 

solid 

solid 
solid 

liquid 

liquid 

liquid 

liquid 
liquid 



3. On the Swelling of Fibrin in Polybasic Acids and their Salts 1 

In order to show that the swelling (and solution) of gelatin in 
the presence of so-called " buffer" salts is not exceptional, the 
following experiments on fibrin were undertaken. They show that 
the same general law holds for the absorption of water by this 
protein. 

§ 1 

The fibrin was a preparation carefully prepared from blood and 
thoroughly washed to remove as many adhering salts as possible. 

1 Martin H. Fischer and Martin Benzinger: Science, 46, 189 (1917); 
Jour. Am. Chem. Soc, 40, 292 (1918) 



NEPHRITIS 



603 



After being dried at a low temperature it was pulverized in a 
mortar. Weighed amounts of the powder (0.5 gram) were then 



/ 



/ 



/ 




introduced into definite volumes (20 cc.) of the various solutions 
employed, contained in calibrated test tubes of uniform diameter 



604 



(EDEMA AND NEPHRITIS 



TABLE CXXII 

Gelatin — Sodium bicarbonate through sodium carbonate to sodium hydroxid 



Concentration of solution. 


■Physical 
state. 


(x) 5 cc. 2% gelatin +5.00 cc. H2O (control) 


... 
solid 


(1) 5 cc. 2% gelatin +0.20 cc. m/1 NaHC03 +4.80 cc. H2O 


solid 


(2) 5 cc. 2% gelatin +0.18 cc. m/1 NaHC03 + 0.02 cc. m/1 Na2C03 + 4.8 




cc. H2O 


... 
so id 


(3) 5 cc. 2% gelatin +0.16 cc. m/1 NaHCO3 + 0.04 cc. m/1 Na2C03 +4.8 




cc. H2O 


... 
solid 


(4) 5 cc. 2% gelatin + 0.14 cc. m/1 NaHC03 + 0.06 cc. m/1 Na2C03 + 4.8 




cc. H2O 


... 
so 1 


(5) 5 cc. 2% gelatin + 0.12 cc. m/1 NaHCCk + 0.08 cc. m/1 Na2C03' + 4.8 




cc. H2O 


... 
80 1 


(6) 5 cc. 2% gelatin + 0.10 cc. m/1 NaHCO3 + 0.10 cc t m/1 Na2C03 +4.8 




cc. H2O 


... 

so 


(7) 5 cc. 2% gelatin + 0.08 cc. m/1 NaHCO3 + 0.12 cc. m/1 Na2C03 + 4.8 




cc. H2O 


... 

80 1 


(8) 5 cc. 2% gelatin +0.06 cc. m/1 NaHCO3 + 0.14 cc. m/1 Ka2C03 + 4.8 




cc. H2O 


solid 


(9) 5 cc. 2% gelatin +0.04 cc. m/1 NaHCO3 + 0.16 cc. m/1 Na2C03 +4.8 




cc. H2O 


lid 


(10) 5 cc. 2% gelatin + 0.02 cc. m/1 NaHCO3 + 0.18 cc. m/1 Na2C03 + 4.8 




cc. H2O 


I'd 


(11) 5 cc. 2% gelatin +0.20 cc. m/1 Na2CO3+4.80 cc. H2O 


s°lid 


(12) 5 cc. 2% gelatin +0.18 cc. m/1 Na2C03 +0.02 cc. n/1 NaOH+4.8 cc. 




H2O 


... 

so 


(13) 5 cc. 2% gelatin +0.16 cc. m/1 Na2C03 +0.04 cc. n/1 NaOH +4.8 cc. 




H2O 


solid 


(14) 5 cc. 2% gelatin +0.14 cc. m/1 Na 2 C0 3 +0.06 cc. n/1 NaOH +4.8 cc. 




H2O 


solid 


(15) 5 cc. 2% gelatin +0.12 cc. m/1 Na 2 C03 +0.08 cc. n/1 NaOH +4.8 cc. 




H2O 


semi-solid 


(16) 5 cc. 2% gelatin +0.10 cc. m/1 Na 2 C0 3 +0.10 cc. n/1 NaOH +4.8 cc. 




H2O 


semi-solid 


(17) 5 cc. 2% gelatin +0.08 cc. m/1 Na 2 CO 3 +0.12 cc. n/1 NaOH +4.8 cc. 




H2O 


liquid 


(18) 5 cc. 2% gelatin +0.06 cc. m/1 Na 2 CO3+0.14 cc. n/1 NaOH +4.8 cc. 




H2O 


liquid 


(19) 5 cc. 2% gelatin +0.04 cc. m/1 Na 2 CO 3 +0.16 cc. n/1 NaOH +4.8 cc. 




H2O 


liquid 


(20) 5 cc. 2% gelatin +0.02 cc. m/1 Na 2 CO3+0.18 cc. n/1 NaOH +4.8 cc. 




H2O 


liquid 


(21) 5 cc. 2% gelatin +0.20 cc. n/1 NaOH +4.80 cc. H2O 


liquid 



(1.5 cm.). The same standard solutions of acids, alkali and of 
salts as were employed in the study of gelatin were used. All 
the mixtures in the various tubes were treated in exactly the same 
fashion, as to shaking, settling, etc. The height of the swollen 
fibrin columns, at the end of 24 hours was taken as the index of 
water absorption. The results of our several series of experiments 
may be summed up as follows: 

(a) We tested first the effects of a progressive change from 
monosodium citrate through disodium citrate to trisodium citrate 
in equimolar concentrations, continuing the series toward a pure 



NEPHRITIS 



605 



acid on the one side and toward a pure alkali upon the other side, 
as shown in Table CXXIII. 

As indicated by the heights of the fibrin columns, and better 
by the curve of Fig. 185 which expresses the results of this experi- 
ment graphically, greatest swelling is observed in the pure solu- 
tions of acid or alkali. From these extremes the amount of swell- 




Solution No. 4 



Figure 185. 



ing decreases as neutralization progresses until a low point is" 
reached in the middle of the curve. This low point is observed in 
a mixture of, approximately, one molar equivalent of monosodium 
citrate with two molar equivalents of disodium citrate. In com- 
paring this minimal point for fibrin with that obtained in the case 
of gelatin it is seen that in the latter instance it lies closer to the 
(theoretically) pure solution of monosodium citrate. 



606 



(EDEMA AND NEPHRITIS 



TABLE CXXIII 
Fibrin — Citric acid through citrates to sodium hydroxid 



Concentration of solution. 



Height of 
fibrin column 
in mm. after 

24 hours. 



(1) 2.0 cc. n/1 citric acid +18 cc. H 2 

(2) 1.6 cc. n/1 citric acid +0.4 cc. m/1 monosodium citrate +18 cc. H2O 

(3) 1.2 cc. n/1 citric acid +0.8 cc. m/1 monosodium citrate +18 cc. H2O 

(4) 0.8 cc. n/1 citric acid +1.2 cc. m/1 monosodium citrate +18 cc. H2O 

(5) 0.4 cc. n/1 citric acid +1.6 cc. m/1 monosodium citrate +18 cc. H2O 

(6) 2.0 cc. m/1 monosodium citrate +18 cc. H2O 

(7) 1.6 cc. m/lmonosodiumcitrate+0.4cc.m/ldisodiumcitrate+18cc.H2O 

(8) 1.2 cc. m/lmonosodium citrate +0. 8cc.m/ldisodium citrate +I8CC.H2O 

(9) 0.8 cc m/ 1 monosodium citrate +1.2 cc. m/1 disodium citrate +18 cc H2O 

(10) 0.4 cc. m/lmonosodium citrate +1.6cc.m/ldisodiumcitrate +I8CC.H2O 

(11) 2.0 cc. m/1 disodium citrate +18 cc H2O 

(12) 1.6 cc. m/1 disodium citrate +0.4 cc. m/1 trisodium citrate +18 cc. H2O 

(13) 1.2 cc. m/1 disodium citrate +0.8 cc. m/1 trisodium citrate +18 cc. H2O 

(14) 0.8 cc. m/1 disodium citrate +1.2 cc. m/1 trisodium citrate +18 cc. H2O 

(15) 0.4 cc. m/1 disodium citrate +1.6 cc. m/1 trisodium citrate +18 cc. H2O 

(16) 2.0 cc. m/1 trisodium citrate +18 cc. H2O 

(17) 1.6 cc. m/1 trisodium citrate +0.4 cc. n/1 NaOH+18 cc. H2O 

(18) 1.2 cc. m/1 trisodium citrate +0.8 cc! n/1 NaOH+18 cc. H2O 

(19) 0.8 cc. m/1 trisodium citrate +1.2 cc. n/1 NaOH+18 cc. H 2 

(20) 0.4 cc. m/1 trisodium citrate +1.6 cc. n/1 NaOH+18 cc. H2O 

(21) 2.0 cc. n/1 NaOH+18 cc. H2O 

(22) 20 cc. water (control) 



31.0 

21.5 

16.5 

15. 

14. 

14. 

13. 

13. 

13. 

13. 

12. 

12. 

13.0 

13.5 

17.0 

21.5 

31.0 

47.0 

58.0 

73.0 

96.5 

12.5 



(b) In a next series of experiments we tested the effects of a 
gradual increase in the phosphoric acid content of a solution con- 




Solution Not 4 



10 12 14 
Figure 186. 



taining a fixed amount of disodium phosphate. The results are 
shown in Table CXXIV and Fig. 186. When phosphoric acid is 
added to disodium phosphate there is at first a decrease in the 



NEPHRITIS 607 
TABLE CXXIV 



Fibrin — Disodium phosphate -{-increasing amounts of phosphoric acid 



Concentration of solution. 


Height of 
fibrin column 
in mm. after 

24 hours. 


k-U 


0.8 


cc. 


m /4 'NTaoHPn^ -1-0 44 ro n/1 H?POj4-18 7fi en 

ill/ *± 1>I CX2-L.LX W4 | W . Ti^t Ol^. 11/ X 11 6 1 U4 lO. 1 U KjK*. 


H2O 


20.0 


o\ 

\4) 


0.8 


cc. 


m/4 Na2HPO4+0.42 cc. n/1 H3PO4+I8 78 cc. 


H 2 


19.0 


tv\ 
\p) 


0.8 


cc. 


m /4 NnoTTPO^ 4-0 40 or n/1 HiPO,i 4-1 8 80 

ILL/ *± I* <X2XXX W 4 | W . t£ U 11/ X lldl V4 T^lO.Ou L'L/. 


H2O 


18.0 




0.8 


cc. 


m/4 Na2HPO4+0.38 cc. n/1 H3PO4 +18.82 cc. 


H 2 


18.0 


(5) 


0.8 


cc. 


m/4 Na2HP0 4 +0.36 cc. n/1 H3PO4 +18.84 cc. 


H2O 


18.0 


(K) 
\V) 


0.8 


cc. 


m/4 Na 2 HPO 4 +0.34 cc. n/1 H3PO4 +18.86 cc. 


H 2 


17.5 


(7) 


0.8 


cc. 


m/4 Na 2 HPO 4 +0.32 cc. n/1 H3PO4 + 18.88 cc. 


H 2 


17.0 


(8) 


0.8 


cc. 


m/4 Na 2 HPO 4 +0.30 cc. n/1 H3PO4 +18.90 cc. 


H2O 


16.5 


(9) 


0.8 


cc. 


m/4 Na 2 HPO 4 +0.28 cc. n/1 H3PO4 +18.92 cc. 


H2O 


15.5 


(10) 


0.8 


cc. 


m/4 Na 2 HPO 4 +0.26 cc. n/1 H3PO4 +18.94 cc. 


H2O 


15.0 


(11) 


0.8 cc. 


m/4 Na 2 HPO4+0.24 cc. n/1 H3PO4 +18.96 cc. 


H2O 


14.5 


(12) 


0.8 


cc. 


m/4 Na 2 HPO 4 +0.22 cc. n/1 H3PO4 +18.98 cc. 


H2O 


14.0 


(13) 


0.8 


cc. 


m/4 Na2HPO 4 +0.20 cc. n/1 H3PO4 +19.00 cc. 


H2O 


14.0 


(14) 


0.8 


cc. 


m/4 Na 2 HPO 4 +0.18 cc. n/1 H3PO4 +19.02 cc. 


H2O 


14.0 


(15) 


0.8 


cc. 


m/4 Na 2 HP0 4 +0.16 cc. n/1 H3PO4+I9.O4 cc. 


H2O 


13.5 


(16) 


0.8 


cc. 


m/4 Na 2 HPO 4 +0.14 cc. n/1 H3PO4 +19.06 cc. 


H2O 


14.0 


(17) 


0.8 


cc 


m/4 Na 2 HPO 4 +0.12 cc. n/1 H3PO4 +19.08 cc. 


H2O 


14.0 


(18) 


0.8 


cc. 


m/4 Na 2 HPO 4 +0.10 cc. n/1 H3PO4 +19.10 cc. 


H2O 


14.5 


(19) 


0.8 


cc. 


m/4 Na 2 HPO 4 +0.08 cc. n/1 H3PO4 +19.12 cc. 


H2O 


14.5 


(20) 


0.8 


cc. 


m/4 Na 2 HPO 4 +0.06 cc. n/1 H3PO4 +19.14 cc. 


H2O 


14.5 


(21) 


0.8 cc. 


m/4 Na 2 HPO 4 +0.04 cc. n/1 H 3 P0 4 +19.16 cc. 


H2O 


14.5 


(22) 


0.8 


cc. 


m/4 Na 2 HPO 4 +0.02 cc. n/1 H3PO4 +19.18 cc. 


H2O 


15.5 


(23) 


0.8 


cc. 


m/4 Na 2 HP0 4 + 19.2 cc. H 2 




16.0 


(24) 


20 cc. water (control) 




12.5 



amount of swelling. This gives way later to an increased swell- 
ing as the concentration of the acid passes a certain point. The 
experimental results show that this point of minimal swelling is 
observed in a mixture which theoretically is composed of about 
molar equivalents of disodium phosphate and monosodium 
phosphate. 

(c) In Table CXXV and Fig. 187 are shown the effects of 
adding to the same concentration of disodium phosphate used 
in the previous experiment, progressively greater amounts of 
sodium hydroxid. There is, with every increase in the concen- 
tration of the added alkali, an increase in the height of the 
swelling column. 

(d) The effects of adding progressively greater amounts of 
sodium hydroxid to a fixed amount of monosodium phosphate of 
the same molar concentration as the disodium phosphate used in 
the previous experiments are shown in Table CXXVI and Fig. 
188. When small amounts of the alkali are added to the monoso- 
dium phosphate there is to be observed at first a decrease in the 



608 (EDEMA AND NEPHRITIS 



TABLE CXXV 

Fibrin — Disodium phosphate -{-increasing amounts of sodium hydrorid 



Concentration of solution. 


Height of 
fibrin column 
in mm. after 

24 hours. 


(1) 


0.8 cc. m/4 Na 2 HP0 4 +19.2 cc. H 2 


16.0 


(2) 


0.8 cc. m/4 Na 2 HP0 4 + 0.02 cc. n/1 NaOH +19.18 cc. H 2 


16.5 


(3) 


0.8 cc. m/4 Xa 2 HP0 4 + 0.04 cc. n 1 XaOH +19.16 cc. H 2 


17.5 


(4) 


0.8 cc. m/4 Xa 2 HP0 4 + 0.06 cc. n/1 NaOH +19.14 cc. H 2 


18.5 


(5) 


0.8 cc. m/4 Na 2 HP0 4 + 0.08 cc. n/1 NaOH +19.12 cc. H 2 


19.5 


(6) 


0.8 cc. m/4 Na 2 HP0 4 + 0.10 cc. n/1 NaOH +19.10 cc. H 2 


21.0 


(7) 


0.8 cc. m/4 Na 2 HPOi+ 0.12 cc. n/1 NaOH +19.08 cc. H 2 


22.0 


(8) 


0.8 cc. m/4 Na 2 HP0 4 + 0.14 cc. n/1 NaOH +19.06 cc. H 2 


23.0 


(9) 


0.8 cc. m/4 Na 2 HP0 4 + 0.16 cc. n/1 NaOH +19.04 cc. H 2 


24.5 


(10) 


0.8 cc. m/4 Na 2 HP0 4 + 0.18 cc. n/1 NaOH +19.02 cc. H 2 


26.5 


(11) 


0.8 cc m/4 Na 2 HP0 4 + 0.20 cc. n/1 NaOH +19.00 cc. H 2 


29.5 


(12) 


0.8 cc. m/4 Na 2 HP0 4 + 0.22 cc. n/1 NaOH +18.98 cc. H 2 


34.5 


(13) 


20 cc. water (control) 


12.5 



32 
28 
24 
20 
15 
12 
8 
4 



Solution No. 4 6 8 10 12 
Figure 187. 

amount of swelling which later, however, with further increase in 
the amount of alkali added, gives way to an increased swelling. 
It is again obvious that the low point in the swelling curve is found 




NEPHRITIS 



609 



TABLE CXXVI 

Fibrin — Monosodium phosphate -{-increasing amounts of sodium hydroxid 



Concentration of solution. 



Height of 
fibrin column 
in mm. after 

24 hours. 



(1) 0.2 cc. 

(2) 0.2 cc. 

(3) 0.2 cc. 

(4) 0.2 cc. 

(5) 0.2 cc. 

(6) 0.2 cc. 

(7) 2 cc. 

(8) 0.2 cc. 

(9) 0.2 cc. 

(10) 0.2 cc. 

(11) 0.2 cc. 

(12) 0.2 cc. 

(13) 0.2 cc. 

(14) 0.2 cc. 

(15) 0.2 cc. 

(16) 0.2 cc. 

(17) 0.2 cc. 

(18) 0.2 cc. 

(19) 0.2 cc. 

(20) 0.2 cc. 

(21) 20 cc. 



m/1 NaH 2 P04+19 
m/1 NaH 2 P0 4 + 
m/1 NaH 2 P04+ 
m/1 NaH 2 P04+ 
m/1 NaH 2 P04+ 
m/1 NaH 2 P0 4 -l- 
m/1 NaH 2 P0 4 + 
m/1 NaH 2 P0 4 + 
m/1 NaH 2 P04+ 
m/1 NaH 2 P04+ 
m/1 NaH 2 P04+ 
m/1 NaH 2 P04+ 
m/1 NaH 2 P04+ 
m/1 NaH 2 P04 + 
m/1 NaH 2 P0 4 + 
m/1 NaH 2 P04 + 
m/1 NaH 2 P04 + 
m/1 NaH 2 P0 4 + 
m/1 NaH 2 P0 4 + 
m/1 NaII 2 P04 + 
water (control) 



80 cc. 
02 cc 
04 cc. 
06 cc. 
08 cc. 
10 cc. 
12 cc. 
14 cc, 
16 cc, 
18 cc, 
20 cc. 
22 cc. 
24 cc. 
26 cc 
28 cc. 
.30 cc 
32 cc 
34 cc. 
36 cc 
38 cc, 



H 2 

n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH+19 
n/1 NaOH +19 



.78 cc. 
.76 cc. 
.74 cc. 
.72 cc. 
.70 cc. 
.68 cc. 
.66 cc. 
.64 cc. 
.62 cc. 
.60 cc. 
.58 cc. 
.56 cc. 
.54 cc. 
.52 cc. 
.50 cc. 
.48 cc. 
.46 cc. 
.44 cc. 
.42 cc 



H2O 
H 2 
H 2 
H 2 
H 2 
HzO 
H 2 
H 2 
H2O 
H 2 
H2O 
H 2 
H 2 
H 2 
H 2 
H2O 
H2O 
H 2 
H2O 



16.0 

15.5 

15.5 

15.5 

15.0 

15.0 

14.0 

15.0 

15.5 

15.5 

15.5 

16.0 

16.5 

18.0 

19.5 

21, 

23. 

25. 

27. 

33. 

12. 




Solution No. 4 



10 12 
Figure 188. 



at a point at which the mixture is essentially one of molar equiva- 
lents of monosodium and disodium phosphate. 



610 



(EDEMA AND NEPHRITIS 



TABLE CXXVII 



Fibrin — Phosphoric acid -{-increasing amounts of sodium hydroxid 



Concentration of solution. 


Height of 
fibrin column 
in mm. after 

24 hours. 


(1) 


o.e 


cc. 


n/1 


H3PO4+O.O2 cc. n/1 NaOH +19.38 cc. H 2 


16 


5 


(2) 


o.e 


cc. 


n/1 


H3PO4+O.O4 cc. n/1 NaOH +19.36 cc. H2O 


15 


5 


(3) 


0.6 cc. 


n/1 


H3PO4+O.O6 cc. n/1 NaOH +19.34 cc. H 2 


15 





(4) 


o.e 


cc. 


n/1 


H3PO4+O.O8 cc. n/1 NaOH +19.32 cc. H 2 


14 


5 


(5) 


o.e 


cc. 


n/1 


H3PO4+O.IO cc. n/1 NaOH +19.30 cc. H2O 


14 





(6) 


o.e 


cc. 


n/1 


H3PO4+O.I2 cc. n/1 NaOH +19.28 cc. H 2 


13 





(7) 


o.e 


cc. 


n/1 


H3PO4+O.I4 cc. n/1 NaOH +19.26 cc. H2O 


12 


5 


(8) 


o.e 


cc. 


n/1 


H3PO4+O.I6 cc. n/1 NaOH +19.24 cc. H2O 


12 


5 


(9) 


o.e 


cc. 


n/1 


H3PO4+O.I8 cc. n/1 NaOH +19.22 cc. H 2 


12 


5 


(10) 


0.6 


cc. 


n/1 


H3PO4+O.2O cc. n/1 NaOH +19.20 cc. H2O 


12 


5 


(11) 


0.6 


cc. 


n/1 


H3PO4+O.22 cc. n/1 NaOH +19.18 cc. H 2 


12 


5 


(12) 


0.6 


cc. 


n/1 


H3PO4+O.24 cc. n/1 NaOH +19.16 cc. H2O 


12 


5 


(13) 


0.6 


cc. 


n/1 


H3PO4+O.26 cc. n/1 NaOH +19.14 cc. H2O 


12 


5 


(14) 


0.6 


cc. 


n/1 


H3PO4+O.28 cc. n/1 NaOH +19.12 cc. H2O 


12 


5 


(15) 


0.6 


cc. 


n/1 


H3PO4+O.3O cc. n/1 NaOH +19.10 cc. H 2 


12 


5 


(16) 


0.6 


cc. 


n/1 


H3PO4+O.32 cc. n/1 NaOH +19.08 cc. H2O 


12 


5 


(17) 


0.6 cc. 


n/1 


H3PO4+O.34 cc. n/1 NaOH +19.06 cc. H 2 


12 


5 


(18) 


0.6 


cc. 


n/1 


H3PO4+O.36 cc. n/1 NaOH +19.04 cc. H2O 


12 


5 


(19) 


0.6 


cc. 


n/1 


H3PO4+O.38 cc. n/1 NaOH +19.02 cc. H 2 


12 


5 


(20) 


0.6 


cc. 


n/1 


H3PO4+O.4O cc. n/1 NaOH +19.00 cc. H2O 


13 





(21) 


o.e 


cc. 


n/1 


H3PO4+O.42 cc. n/1 NaOH +18.98 cc. H2O 


14 


5 


(22) 


0.6 


cc. 


n/1 


H3PO4+O.44 cc. n/1 NaOH +18.96 cc. H 2 


15 





(23) 


o.e 


cc. 


n/1 


H3PO4+O.46 cc. n/1 NaOH +18.94 cc. H2O 


16 





(24) 


o.e 


cc. 


n/1 


H3PO4+O.48 cc. n/1 NaOH +18.92 cc. H2O 


17 





(25) 


o.e 


cc. 


n/1 


H3PO4+O.5O cc. n/1 NaOH +18.90 cc. H 2 


75 


0(?) 


(26) 


o.e 


cc. 


n/1 


H3PO4+O.52 cc. n/1 NaOH +18.88 cc. H2O 


17 


5 


(27) 


o.e 


cc. 


n/1 


H3PO4+O.54 cc. n/1 NaOH +18.86 cc. H2O 


17 


5 


(28) 


o.e 


cc. 


n/1 


H3PO4+O.56 cc. n/1 NaOH +18.84 cc. H2O 


18 





(29) 


,o.e 


cc. 


n/1 


H3PO4+O.58 cc. n/1 NaOH +18.82 cc. H2O 


20 





(30) 


o.e 


cc. 


n/1 


H3PO4+O.6O cc. n/1 NaOH +18.80 cc. H 2 


26 





(31) 


o.e 


cc. 


n/1 


H3PO4+O.62 cc. n/1 NaOH +18.78 cc. H2O 


30 





(32) 


o.e 


cc. 


n/1 


H3PO4+O.64 cc. n/1 NaOH +18.76 cc. H2O 


24 





(33) 


20 cc. water (control) 


12 


5 



(e) The results of another type of variation in experimental 
procedure is shown in Table CXXVII and Fig. 189. Here a fixed 
amount of phosphoric acid has added to it progressively greater 
amounts of sodium hydroxid. This arrangement allows us to 
see the effects of simultaneously reducing acid content while 
increasing the amount and kind of phosphate present. The result 
is again, however, a curve of the same general type already dis- 
cussed. Beginning with the greatest swelling in the pure acid 
there is a gradual fall in the curve until a low point is reached in a 
mixture lying midway between the (theoretically) pure monoso- 
dium phosphate and the pure disodium phosphate. 

(/) A final type of variation in experimental procedure is 
shown in Table CXXVIII and Fig. 190. Here a fixed amount 



NEPHRITIS 



611 



of alkali has added to it progressively greater amounts of phos- 
phoric acid until neutralization is carried to the point of get- 




B 

ting a (theoretically) pure solution of trisodium phosphate. 
The progressive decrease in the amount of swelling with de- 
crease in alkalinity and increase in phosphate content is readily 
apparent. 



612 



(EDEMA AND NEPHRITIS 



TABLE CXXVIII 



Fibrin — Sodium hydroxid-r increasing amounts of phosphoric acid 



Concentration of solution. 


fibrin column 
in mm. after 

24 hnnrs; 


(1) 


0( 


> cc. n/1 NaOH+0.60 cc. n 


1 H3PO4 +18.80 cc. H2O 


23 .0 


(2) 


O.f 


> cc. n/1 NaOH +0.58 cc. n 


1 H3PO4 +18.82 cc. H2O 


23.5 


(3) 


D.< 


> cc. n/1 NaOH +0.54 cc. n 


1 H3PO4 +18.86 cc. H2O 


25.5 


(4) 


O.C 


» cc. n/1 NaOH +0.50 cc. n 


1 H3PO4 +18.90 cc. H2O 


28.0 


(5) O.e 


» cc. n/1 NaOH +0.46 cc. n 


1 H3PO4 +18.94 cc. H2O 


32.5 


(6) 


o.e 


ec. n/1 NaOH +0.42 cc. n 


1 H3PO4 +18.98 cc. H2O 


35.5 


(7) 


O.C 


cc. n/1 NaOH +0.38 cc. n 


1 H3PO4 +19.02 cc. H»0 


40.5 


(8) 


o.e 


cc. n/1 NaOH +0.34 cc. n 


1 H.3PO4 +19.06 cc. H2O 


41.0 


(9) 


o.e 


cc. n/1 NaOH +0.30 cc. n 


1 H3PO4 +19.10 cc. H2O 


45.0 


(10) 


0.€ 


cc. n/1 NaOH +0.26 cc. n 


1 H3PO4 +19.14 cc. H2O 


47.5 


(ID 


0.6 


cc. n/1 NaOH +0.22 cc. n 


1 H3PO4 +19.18 cc. H2O 


52.0 


(12) 


o.e 


cc. n/1 NaOH +0.18 cc. n, 


1 H3PO4 +19.22 cc. H2O 


59.0 


(13) 


0.6 cc. n/1 NaOH +0.14 cc. n, 


1 H3PO4 +19.26 cc. H2O 


62.0 


(14) 


0.6 


cc. n/1 NaOH +0.10 cc. n/ 


1 H3PO4 +19.30 cc. H2O 


63.5 


do) 


0.€ 


cc. n/1 NaOH +0.06 cc. n 


1 H3PO4 +19.34 cc. H2O 


68.0 


(16) 


0.6 


cc. n/1 NaOH +0.02 cc. n, 


1 H3PO4 +19.38 cc. H2O 


75.0 


(17) 


20 


cc. water (control) 




12.5 



§ 2 

The experimental findings detailed in these paragraphs with 
those previously outlined for gelatin, bring out the fact that the 
minimal points of water absorption in citrate and phosphate mix- 
tures are different for the two proteins. While the minimal swell- 
ing point for gelatin is found in a mixture closely approximating 
one of pure monosodium citrate or pure monosodium phosphate, 
the minimal one for fibrin is found at a point represented more 
nearly by a mixture of molar equivalents of the mono- and di- 
salts of these two acids. Such differences in the behavior of 
various proteins must be kept in mind when these experiments on 
simple protein colloids are applied to biological material. Proto- 
plasm represents, according to present beliefs, a mixture of at 
least two and probably several different proteins. 

We hold that these results on fibrin with those already 
detailed on the swelling of gelatin in polybasic acids and their 
salts, corroborate and amplify the ideas previously expressed 
regarding the importance of acids, of alkalies, of various salts, and 
of these in mixture in determining the amount of water absorbed 
by protoplasm under physiological and pathological conditions. 
The well-established qualitative and quantitative analogies 
between the absorption of water by various hydrophilic colloids 



NEPHRITIS 




Figure 190. 



614 



(EDEMA AND NEPHRITIS 



(like the proteins) and isolated cells, organs or organisms, whether 
of animal or vegetable origin, show that the problem of water 
absorption is essentially a colloid-chemical phenomenon. These 
studies with polybasic acids and their salts permit us to re-empha- 
size the importance of an abnormal production or accumulation of 
acids within such colloid systems for increasing the amount of 
water thus held and this independently of the fact that such 
accumulation of acid may occur in the presence or in the absence 
of so-called "buffer" salts. 1 Through the accumulation or pro- 
duction in protoplasm of an abnormally great amount of acid (or 
of alkali), we are thus enabled to explain the mechanism by which 
the abnormally high hydrations of living cells are brought about 
as such are observed in the excessive turgors of plant tissues, in 
the cedemas which involve the animal body, or in those " diseases" 
now to be discussed which are in essence only cedemas of certain 
organs, like nephritis (cedema of the kidney), glaucoma (oedema 
of the eye) or " uremia" (cedema of the brain). 

VIII 

ON THE ALLEGED CONSEQUENCES OF KIDNEY DISEASE 

We need again to break into our main argument here show- 
ing how the factor of acid production acting upon the colloids 
of the kidney leads to the signs and symptoms of nephritis to 
discuss the alleged consequences of kidney disease. Until we 
have disposed of this question we shall not be of one mind on 
certain points where agreement must be reached before progress 
can be made. Many of the clinical manifestations observed in 
patients having kidney disease are considered consequences of the 
impaired kidney function. There are consequences to such impair- 
ment, but almost without exception all those most generally regarded 
as such do not belong in the group. Dogmatic teaching and the 
inertia of time have woven here a tangled skein, but if we will 
consider these alleged consequences separately and logically, 
order can easily be established. 

1 L. J. Henderson (Jour. Am. Chem. Soc, 40, 857 (1918)) is still uncon- 
vinced of this. My reply to' his criticisms, for which there is not space in 
this volume, may be found in Jour. Am. Chem. Soc, 40, 862 (1918). 



NEPHRITIS 



615 



1. On the Relation of Vascular Disease to Nephritis 

§ 1 

It has long been recognized that vascular disease, increased 
blood pressure and cardiac hypertrophy are frequently asso- 
ciated with changes in the kidney which in the aggregate lead to 
the morphological picture which we call chronic interstitial 
nephritis. It is also quite generally accepted that such blood 
vessel disease, hypertrophy and increased blood pressure are 
consequent upon the kidney disease in the sense that impairment 
of function is supposed to permit poisonous substances to accu- 
mulate in the blood, which in addition to producing destructive 
lesions in the blood vessels themselves lead also to the cardiac 
hypertrophy and high blood pressure. This conception with 
all its various modifications is fundamentally wrong. Neither 
logic nor experiment support it and everything argues against 
it. The primary disturbance in chronic interstitial nephritis 
associated with vascular disease and changes in the heart is the 
vascular disease, and the changes in the kidneys, in the heart and 
in the other organs of the body are secondary to it. 

No one has as yet produced in animals a chronic interstitial 
nephritis associated with vascular disease and a hypertrophy 
of the heart. By injecting various poisons into animals, such as 
the salts of the heavy metals, it has been possible to produce 
a chronic interstitial type of nephritis, but the animals show no 
changes in their vascular system and no hypertrophy of the 
heart. These kidneys really correspond to the chronic interstitial 
types of nephritis which we see in human beings who have passed 
through a generalized parenchymatous nephritis due to an intoxi- 
cation of some sort and in whom pieces of the kidney have been 
lost with secondary contracture. We do not as yet possess any 
experimental method of producing in animals vascular disease 
as observed in man and not until we do, need we expect to observe 
a cardiac hypertrophy, increased blood pressure and destructive 
lesions in the kidney which correspond with the changes observed 
in human beings. 

The current notion that vascular change, high blood pressure, 
etc., are secondary to kidney disease can easily be tested out 
experimentally. When we observe such signs and symptoms 



616 



(EDEMA AND NEPHRITIS 



in a human being, the patient is, of course, still alive. He must 
in consequence have sufficient kidney substance available to 
live. It is an easy matter experimentally to reduce the kidney 
substance of an animal down to the physiological minimum. 
If the current opinions were correct such animals should show 
vascular changes, high blood pressure and cardiac hypertrophy, 
but as a matter of fact they show none of them. In Figs. 191, 
192, and 193 are shown the photographs of a series of rabbits 
in which the kidney substance was thus reduced. A wedge 
was first taken out of one kidney so as to reduce its volume one- 




Figure 191. 



half or even more, and then after complete recovery from the 
effects of this operation the whole of the opposite kidney was 
removed. The animals had therefore but one-fourth to one- 
eighth their total kidney substance left. We kept these animals 
in the laboratory for more than five years — a period which easily 
represents over two-thirds their total life expectancy. They 
constituted our breeding stock and were perfectly normal until 
accidentally killed by a bulldog which got at large. In Fig. 191 are 
shown three breeding males, in Figs. 192 and 193 two mothers 
of this series with their families. 

Lest it be thought that such facts hold only for the herbivora 
the following facts regarding some dogs and rats which had a 



NEPHRITIS 



617 



similar reduction in kidney tissue and which were none the worse 
for it are of interest. " Nellie, " a mongrel pup, suffered a removal 
of one-third her right kidney April 9, 1913. The whole of the 
opposite kidney was removed May 19, 1913. After having had a 
family in the interim, this dog was exhibited as a normal creature 
(see Fig. 194) at the scientific exhibit of the American Medical 
Association in San Francisco in 1915. She continued well, mother- 
ing three further litters (see Fig. 195) until May 8, 1919, when she 
died of intestinal obstruction due to a hernia of the ileum into the 
left kidney wound. Save for a transverse scar the remaining 




Figure 192 



fraction of kidney was normal and there were no changes in the 
heart or blood vessels. 

"Blackie," a young mongrel dog, had one half her right kidney 
removed October 10, 1914, and the whole of the opposite one 
November 10. This dog is still alive (October 16, 1920) and well, 
having had some half dozen litters in the meantime, two of which 
(photographed respectively March 20, 1918, and October 20, 1918) 
are shown with the mother in Figs. 196 and 197. 

Rats also continue entirely normal after removal of three- 
quarters their total kidney substance. We have kept both male 
and female rats thus operated upon (Figs. 198 and 199) for more 
than two years in the laboratory which covers the major portion 



618 



(EDEMA AND NEPHRITIS 



of their life expectancy. In spite of the type of food fed (we 
kept large numbers on a purely " meat' 1 diet) none of the animals 
ever showed any changes in their vascular system. 

There is only one way in which the results of these experiments 

F Wk 




CO 

OS 



can be interpreted. Loss of kidney function does not lead to vas- 
cular disease and cardiac hypertrophy, nor to the high blood pressure 
or the other signs so frequently attributed to chronic interstitial ne- 
phritis. 

Once we begin to look upon the vascular disease as the primary 
cause of the nephritis, the cardiac hypertrophy, etc., we encoun- 



NEPHRITIS 



619 



ter no difficulty in interpreting these. As is well known, the 
primary changes in vascular disease occur in the smaller blood 
vessels. When vascular disease attacks the large blood vessels 
it is through the small blood vessels which supply their coats. 
In consequence of the (thrombotic) changes occurring in the 
small vessels circumscribed areas situated in the large blood 
vessels suffer swelling, fatty changes, softening and scarring. The 
mixture constitutes the ordinary picture of vascular "degen- 




Figure 194. 



eration." As similar (thrombotic) changes occur in the various 
organs, the spots thus deprived of a proper blood supply also 
" degenerate." If the attack happens to be made upon the kid- 
ney, spots of dying kidney tissue appear scattered through an 
otherwise healthy-looking kidney. This is the picture of chronic 
interstitial nephritis associated with vascular disease, in which 
pathological entity it is always the rule to find the greatest variety 
of morphological changes. While certain regions are entirely 
normal in appearance, others show characteristic " degenerative" 




Figure 196 



NEPHRITIS 



621 



changes, as evidenced by the presence of cells that are swollen 
and granular, or perhaps have lost their nuclei and are dis- 
integrated (localized parenchymatous nephritis). To take the 
place of the dead cells we may find new parenchyma cells form- 




Figure 197. 

ing, or there may be evidences of connective tissue proliferation, 
indicating the ultimate formation of a scar. 

This patchy appearance, resulting from a mixture of nor- 
mal, degenerating and regenerating cellular elements in the 
kidney, stands in marked contrast to the uniformity of appear- 
ance presented by a kidney that has been poisoned, say, with 
the toxins of an acute infectious disease. Here in a certain 
sense, all parts of the kidney are affected and to about the 
same degree. The appearances correspond with the fact that 
in the first case small patches of the kidneys are successively 
affected by local disturbances in the circulation in the kidney, 
in the second all the cells are at once subjected to the same 
destructive agent. These facts can be interpreted only by rec- 
ognizing a local cause for the spots of (parenchymatous) nephritis, 
and this spotty cause resides in the vascular changes. They 
are the cause of the nephritis and not the other way about. 



622 



(EDEMA AND NEPHRITIS 



It also becomes intelligible why little albumin, and few casts 
go with these types of chronic interstitial nephritis and why the 
output of water remains normal or, as some say, is even increased. 




Figure 198. 



There is plenty of healthy parenchyma left to secrete the normal 
amount of water and the spots of parenchyma affected path- 




Figure 199 



ologically give rise to but few cases and little albumin. Nor 
need the urine of such a nephritic be as highly acid as that 
of the frankly parenchymatous types, for it is the product of 



NEPHRITIS 



623 



that coming from healthy kidney mixed with that secreted by 
the nephritic spots. 

§ 2 

Just as the arteriosclerosis associated with kidney disease 
is not its consequence, but its cause, so the hypertrophy of the 
heart observed in such cases is not the consequence of the kidney, 
but of the blood vessel disease. This is clearly proved by the 
fact that the (physiologically) worst types of nephritis are those 
least liable to be associated with any hypertrophy of the heart. 
We do not find hypertrophied hearts in patients with a gen- 
eralized parenchymatous nephritis, even though they may for 
years have suffered from this. Even gradual destruction of the 
kidneys is not followed by heart hypertrophy. I have under 
observation a man from whom one kidney was removed for 
infection eight years ago and who has had constantly since 
then large numbers of casts and much albumin in the urine 
from the remaining kidney. In spite of the evident destruction 
of much kidney substance he has no heart hypertrophy and a 
systolic blood pressure of 126 with a diastolic of 90 mm. of 
mercury. That, on the other hand, enormous hypertrophies 
of the heart may be associated with no kidney symptoms what- 
soever is familiar to everyone. 

In this subject of heart hypertrophy and chronic interstitial 
nephritis we seem, as clinicians, all too often to lose sight of the 
fact that the hypertrophy results in this case, as in any case, 
from the increased demand for work and the increased rate at 
which a given amount of work must be done. In the hyper- 
trophy associated with arteriosclerosis these are determined by 
at least two changes in the circulation: the reduction in the 
caliber of the blood vessels and the loss of the elasticity of the 
blood vessel walls. 

It should be clearly borne in mind that such roughening of 
the blood vessel walls as is observed has nothing to do with 
increasing the work of the heart. The friction encountered in 
driving the blood through the vessels is not that of blood against 
blood vessel wall, for since the blood " wets " the walls the 
friction is that of one layer of liquid over another. 

With a given kind of blood, the blood vessels determine 
how much work and power is required to force the blood through 
them, only so far as their length (constant in body), diameter, 



624 



(EDEMA AND NEPHRITIS 



and elasticity are concerned. So far as the effect of changes in 
diameter is concerned (and in vascular disease the diameter of 
the blood vessels is diminished not only permanently because of 
vascular thickenings but also more or- less intermittently by con- 
traction (spasm) of the blood vessel coats), it must be borne in mind 
that the force required to drive a given volume of liquid through 
a tube increases about as the cube when the cross -section 
is diminished one-half. The loss of elasticity becomes a factor 
because, under physiological conditions, in the time of a single 
contraction of the ventricle an amount of blood, the equivalent 
of that ejected from the heart, is not at once pushed along the 
entire arterial and capillary bed out into the veins. Under 
normal circumstances it is simply thrown into the elastic arterial 
system, .which dilates somewhat, and then, during the period 
that follows the systole of the heart, the elastic forces resident 
in the arteries slowly recoil and squeeze the blood out into 
the veins. When this elasticity is markedly diminished, the 
heart must in that proportion force its quota of blood during the 
time of each systole at once through the whole arterial and capil- 
lary system. In other words, the heart must do an amount of 
work in the time of the systole which it ordinarily does in the 
time of a systole plus a diastole plus the pause — roughly, say, in 
a third the time. To meet such a contract requires in engineer- 
ing practice a three times larger engine, and the hypertrophied 
heart of the patient with sclerotic arteries represents the same 
idea put to work in nature. 

A third factor tending to increase the demands upon the 
heart and so inducing its hypertrophy might reside in the blood 
itself. A liquid moves through a tube with greater and greater 
difficulty the more viscid it is. Anything that increases the 
viscosity of the blood, therefore, increases the amount of work 
demanded of the heart to push the blood forward. The viscosity 
of such colloid solutions as the blood is enormously increased 
by slight traces of acid 1 (P. von Schroeder, 2 W. B. Hardy 3 
and especially Wolfgang Pauei and Hans Handovsky 4 ) and 
so this factor which comes into play, not only in nephritis, but 

1 See page 145. 

2 P. vox Schroeder: Zeitschr. f. physik. Chem., 45, 106 (1903). 

3 W. B. Hardy: Jour. Physiol., 33, 251 (1905); Proc. Royal Society, 
London, 79, 413 (1907). 

4 Wo. Pauli and H. Handovsky: Biochem. Zeitschr., 18, 340 (1909). 



NEPHRITIS 



625 



in hard work of any kind (laborers, athletes) needs to be con- 
sidered. While certain clinical studies of blood viscosity have 
not yet brought proof that this undergoes any material change 
in nephritis, that such changes might well be expected is indicated 
by certain experiments of R. Bukton-Opitz, 1 who found venous 
blood to have a higher viscosity than arterial, due to the carbonic 
acid in it, and the blood of dogs after the feeding of proteins (acid 
production) to have a higher viscosity than before such feeding. 

§ 3 

From what has been said it is clear that we cannot regard 
the heart hypertrophy as something primary, but as something 
secondary — as an example of the wide range of adaptation to 
changed conditions of which the cells and organs of our body 
are capable. Neither can we any longer consider the high blood 
pressure found in these cases and made possible through the for- 
tunate possession of a larger and more effectively working pump 
as something bad. The high blood pressure is decidedly good, for 
only through the increased pressure are the various tissues of the 
body guaranteed a blood supply sufficient to satisfy their physiolo- 
gical demands. This holds for the kidney as for any other organ 
in the body. Only the increased blood pressure renders it possible 
that the normal parts remaining in an arteriosclerotic kidney 
maintain their normal activity. While conditions may exist 
or arise in the body which make the high blood pressure in itself 
dangerous (weakening of blood vessel walls and rupture), a high 
blood pressure must with this exception not be regarded as something 
'evil, but as an attempt on the part of the body to keep our various 
organs working at their physiological optimum. Measures that 
merely reduce blood pressure can, therefore, hardly be looked 
upon with favor. We must treat the underlying cause of the 
increased blood pressure, not the blood pressure itself. To apply 
this to the kidney, with which we happen to be dealing, I can 
recall several cases of chronic interstitial nephritis with high 
blood pressure and cardiac hypertrophy in which a too enthusi- 
astic desire to reduce the blood pressure led to the use of the 
nitrites, and with serious consequences. While the blood pressure 
fell, the urinary output also decreased, the albumin rose and casts 
J R. Burton-Opitz: Pfliiger's Arch., 119, 359 (1907). 



626 



(EDEMA AND NEPHRITIS 



became numerous. In other words, the general fall in blood 
pressure made for a decreased circulation of blood through the 
kidney, and so for an aggravation of the kidney state. Only 
when we think that such a bad result will not follow the use of 
nitrites are we justified in using them. One case developed 
immediately after a single dose of amyl nitrite a complete anuria 
which some eight days later killed the patient. 

2. On the (Edema of Nephritis 

As far as I know, it is universally held that the cedema, often 
of extreme grade, so commonly found in nephritis is secondary 
to the kidney condition. We are especially prone to find a 
generalized cedema in the so-called parenchymatous types of 
nephritis. (Edema is not observed in the chronic interstitial 
nephritides associated with vascular disease except in the ter- 
minal stages. Why it occurs then will be discussed later. To 
avoid confusion we will temporarily limit ourselves to a discussion 
of the cedema so commonly observed in the frankly parenchym- 
atous types. According to the prevailing notion, the cedema of 
the body generally is held to be secondary to the loss of kidney 
function. It is argued, in other words, that in an acute or chronic 
parenchymatous nephritis the kidneys are unable to excrete 
water properly and that this is, therefore, retained in the body 
with resulting cedema. 

This view is also fundamentally wrong. If it were true that 
the cedema is secondary to the loss of kidney func+ion, then we 
should be able, experimentally, to produce an oedema most 
rapidly by cutting the kidneys away. But when we take both 
kidneys out of an animal under light ether anesthesia, it recovers 
rapidly and continues to live for many days thereafter In all 
this time it does not develop a particle of cedema, in fact, it steadily 
loses in weight. The one sign it shows is a progressive weakness, 
and finally it dies quietly. 

Nature has performed this experiment many times in human 
beings, and what these show agrees absolutely with what is 
observed in the animals just described. Thus, after removal 
of an only kidney or after occlusion of both ureters by stone, 
or similar accidents which do away at once with the excretory 
function of the kidneys, the patient shows none of the signs of 



NEPHRITIS 



627 



a generalized oedema, nor, as we shall see later, any of the many 
other alleged consequences of loss of kidney function. Patients 
so affected have lived many days, and during this time have 
showed nothing but a progressive loss of weight and - strength. 
James Taggart Priestley has reported the case of a man who 
lived thus for twenty-two days. There is only one way in which 
these constant and unequivocal results can be explained. The 
oedema observed in nephritis is not secondary to the loss of kidney 
function. Kidney disease does not lead to the development of oedema. 

How then are we to interpret the combination of a general- 
ized oedema with a nephritis? To do this correctly we need 
but consider the results of experiments in which poisons are 
injected into animals which are capable of producing what are 
generally considered the signs and symptoms of a parenchymatous 
nephritis. Uranium constitutes one of the accepted of this class. 
If rabbits or frogs are injected with small doses of a uranium 
salt they show very shortly thereafter the signs and symptoms 
of kidney involvement, as indicated by albumin, casts and 
blood in the urine with a diminution in the urinary output. They 
may be well marked at the end of twelve hours, and in one or 
two days may become so extreme that actual suppression results; 
but even if a fair amount of urinary secretion still persists the 
animals, nevertheless, begin to gain in weight. Thus, frogs show 
an increase in weight at the end of twelve hours, and at the end 
of twenty-four or forty-eight hours may have gained anywhere 
from twenty-five to forty or even fifty per cent in weight. At 
the same time they become sluggish in their movements, respond 
but slightly to stimulation and occasionally die in convulsions. 
In other words, the interference with kidney function may be 
slight as compared with nephrectomy, yet we see in the first 
days of these experiments degrees of oedema which are not encoun- 
tered after total extirpation of the kidneys even if the animal 
or patient lives for weeks. Let us interject here that nephrec- 
tomized animals when injected with uranium develop an oedema 
as pronounced as that of animals with previously normal kidneys. 
How are these results to be explained? 

The oedema of a parenchymatous nephritis is not secondary to 
the kidney disease, but represents in the involved tissues the same 
type of change as that which in the kidney ice call nephritis. The 
swelling of the kidney represents the same process in this organ as 



628 (EDEMA AND NEPHRITIS 

the swelling of the tissues of the body generally, and both of them are 
induced by the same cause. The intoxication which affected the 
kidney affected at the same time all the other tissues of the body 
and as it induced the swelling of the kidney with the other signs of 
nephritis, it also induced a swelling of the body tissues generally. 

3. On the " Uremia " of Nephritis 

The experiments and clinical observations discussed in the 
preceding paragraphs may be used to answer some questions 
associated with the problem of uremia. It is quite generally 
held that certain symptoms clinically considered characteristic 
of uremia, such as headache, vomiting, disturbances in vision, 
stupor, at times mania, disturbances in respiration, coma and 
death are secondary to loss of kidney function in the sense that 
a defective eliminatory power of the kidneys is supposed to lead 
to a retention of poisonous substances in the blood, to their 
accumulation in the brain, and so to the signs and symptoms 
just discussed. We will not deny that certain substances nor- 
mally excreted through the urine may and do accumulate in the 
blood and so in the body tissues generally when for any reason 
the excretory function of the kidney is impaired. As is well 
known, however, none of these substances when injected into 
animals have thus far led to a reproduction of the picture which 
clinically goes by the name of uremia. As a matter of fact 
when the kidney function of an animal is done away with 
through double nephrectomy, or when such a condition is observed 
clinically through accident or the agencies of disease, the animal 
or patient shows none of the signs or symptoms generally con- 
sidered uremic. As previously stated, both animals and patients 
suffer throughout their anuric period nothing but a progressive 
loss of strength, while consciousness, mental alertness, vision, 
etc., are maintained to the end. These facts are again inter- 
pretable in only one way: What we call uremia clinically is not 
secondary to loss of kidney function. 

If now we try to say what the " uremia " of the clinicians 
is, then from a pathological point of view we have one solid 
fact upon which to build. Patients dead of it show anatomically 
an oedema of the brain. The signs and symptoms which clinically 
are considered characteristic of uremia are the signs and symptoms 
of an oedema of the central nervous system. The headaches, the 



NEPHRITIS 



629 



mania, the convulsions, the stupor and the coma are to be 
looked upon as signs and symptoms from a swollen brain; the 
blindness as symptomatic of an oedema of the optic nerve or 
retina; the vomiting, disturbed respiration and death as evidence 
of an oedema of the medulla. These cedemas of the central 
nervous system become therefore but part of that cedema which 
affects the rest of the body including the kidney, and underlying 
them all is the same cause. 

The " uremia" observed in chronic interstitial nephritis asso- 
ciated with vascular disease is considered in the next paragraphs. 

4. Reinterpretation of the Relation of Nephritis to the Clinical 
Manifestations Associated Therewith 

With the above ideas in mind it is an easy matter to interpret 
correctly the clinical manifestations accompanying a nephritis, 
and without the self-contradictions which characterize our 
present points of view. The records of the obstetricians are 
filled with reports in which patients showing very slight or no 
urinary findings have nevertheless died in convulsions, while, 
on the other hand, every clinician has seen cases of complete 
abnormal urinary suppression without involvement of the central 
nervous system. On the old basis, according to which the symp- 
toms from the side of the brain were consequent upon kidney 
disease, such findings could not be understood, but they are readily 
intelligible as soon as we recognize that the same poison which 
affects the one organ affects the other also. But a poison circulat- 
ing in the body need not and does not affect all organs equally 
and to the same extent, wherefore it is easily understood that in a 
pregnancy intoxication we may at one time see the brain more 
involved than the kidney, while at another the kidney is more 
seriously affected than the brain. The same line of reasoning 
applies to the other organs of the patient, be they optic nerve, 1 
medulla, or body tissues generally. 

It is only because such organs as the brain, the optic nerve, 
the medulla and the kidney are hampered in their swelling by 

1 E. M. Baehr directed my attention to a football player who after each 
match game would go blind for twenty-four hours with an oedema of the 
optic nerve. As previously noted, an cedema of the kidney (as manifested 
by a decreased urinary output with albumin and casts) is the more obvious 
consequence of the acid intoxication following hard muscular work. 



630 



(EDEMA AND NEPHRITIS 



bony walls and tough capsules that they are most discussed. The 
liver, for example, is quite as commonly affected in a pregnancy 
intoxication as is the brain or kidney, but because its function 
is less obvious and because the capsule is more expansile so that 
a great degree of swelling is rendered possible without ultimately 
destructive effects, this question of liver involvement is not 
so much to the fore. Occasionally, however, the liver destruction 
is of sufficient grade to dominate the clinical picture, and then we 
hear of " altered liver metabolism, " " yellow atrophy of the liver," 
etc. In any general intoxication such as that of pregnancy the 
liver is involved quite as commonly as the other organs' of the 
body and is to be regarded as suffering from the same intoxication 
which is simultaneously attacking the other body structures. 1 

What we have illustrated here by a. pregnancy intoxication 
holds for every general type of intoxication, as with chloroform, 
ether, alcohol, phosphorus, the various heavy metals, and the 
toxins of the infectious diseases. As we shall see later, the 
therapeutic methods which relieve the signs and symptoms 
referable to any one of these organs serve at the same time to 
relieve those referable to every other. Thus, alkalies, magnesium 
sulphate, or calomel, used to reduce the swelling of a liver, are 
likely to improve at the same time the headache, the nausea, 
the vomiting, and the oedema of the body generally, for the intro- 
duction of these substances into that colloid mass which we call 
the body tends to dehydrate all its organs simultaneously. The 
freed water reaching the kidney augments the urinary output. 

We have now to interpret the extrarenal clinical manifesta- 
tions observed in chronic interstitial nephritis. In the atrophic, 
secondarily contracted kidney there may, for reasons discussed 
above, be none at all. We see such extrarenal manifestations 
particularly in the chronic interstitial types found in associa- 
tion with vascular disease. Here again practically none of the 
ordinary signs and symptoms are to be considered secondary 
to the kidney condition. In the early stages of vascular 
disease all the signs and symptoms as observed in the different 

1 The dryness of the skin (lack of sweating) so frequently observed, espe- 
cially in the infectious diseases, is to be similarly interpreted. The same 
poison which affects a kidney and interferes with the output of water by it 
(as in scarlet fever), affects the sweat glands similarly. The return of 
sweating, which the older doctors regarded so favorably, means in the skin 
what an increased urinary output means from the side of the kidney. 



NEPHRITIS 



631 



organs of the body are to be attributed primarily to an involve- 
ment of smaller or larger areas in the different organs of the 
body by the vascular disease. Any one organ, as the kidney, 
may escape entirely. We have already discussed the effects 
of progressive vascular disease as it affects the kidney. In the 
course of years one fragment after another suffers destruction 
with resulting atrophy. The remaining nubbin (" small red 
kidney ") is, of course, subject to the same accidents which 
may affect a normal kidney, and so it is not impossible for it 
at any time to become the seat of a generalized parenchymatous 
nephritis. The " small red kidney " then becomes a " small 
gray kidney." This change is frequently noted in the terminal 
stages of blood vessel disease. Only rarely, however, does the 
involvement of the renal blood vessels themselves become so 
great as to lead to destruction of what remains of kidney sub- 
stance. The reasons for such total destruction usually lie more 
definitely outside the kidney and may reside in intoxications 
similar to those which may affect any kidney. For the most 
part, however, it is dependent upon a failure of the circulation 
with its resultant lack of oxygen to all the tissues of the body, 
an abnormal production and accumulation of acid in them and 
a generalized oedema in which the kidney too is involved. 

Others of the alleged consequences of chronic interstitial 
nephritis can also be intelligently understood as soon as the 
vascular disease is recognized as the primary source of the whole 
clinical picture. This is true, for example, of the hemorrhages 
into the retina and the disturbances in vision so often encoun- 
tered. The " albuminuric retinitis " of the ophthalmologist 
is not the consequence of albuminuria or kidney disease, but 
merely an expression in the eye of the same changes which in the 
kidney give rise to nephritis. The swollen grayish patches or 
the hemorrhages in the eye are the consequence of vascular dis- 
ease, as are the grayish spots and the hemorrhages found in the 
kidney. The ophthalmologist who discovers ocular changes 
should not make the diagnosis of nephritis, but one of vascular 
disease, which may presumably be affecting also the patient's 
kidneys. It should also be emphasized that the eye changes 
observed in conjunction with a frankly parenchymatous neph- 
ritis and those in a chronic interstitial nephritis of the type 
just discussed have a totally different significance. The visual 



632 



(EDEMA AND NEPHRITIS 



changes in the former represent in essence a toxic oedema of 
optic nerve or retina. In the former instance, if the pressure 
from swelling does not become too great or last too long, the 
blindness may therefore be expected to disappear. In the 
second case such complete recovery is largely impossible, for 
here the swelling, the degeneration and hemorrhage both by 
diapedesis and rupture are all too often expressions of irre- 
versibly destructive lesions secondary to irremovable blood 
vessel disease. The distinction between the two conditions is 
analogous to that drawn between generalized parenchymatous 
and chronic interstitial nephritis in our previous discussion. 
While an oedema originally characterizes the involved portions 
in both instances, this is brought about in the one by a removable 
interference with the normal oxidative changes in the involved 
regions as induced by poisons, while in the other it is caused by 
a shutting off of oxygen through narrowed blood vessels which 
cannot be reopened. 

When vascular changes affect the larger blood vessels going 
to the eye the entire globe may become the seat of an oedema. 
This marks the origin of the glaucoma so frequent^ observed 
in patients suffering with vascular disease, a problem which 
receives more detailed discussion later. 1 

How now are we to regard the headache, the vomiting, the 
mania, the coma and convulsions, the altered breathing and 
death, generally diagnosed as uremic, occurring in the course 
of chronic interstitial nephritis? We may observe these changes 
when the patient is suffering from no generalized oedema and when 
the output of water and dissolved substances by the kidneys is 
satisfactory. They are again not secondary to the kidney dis- 
ease, but represent an oedema of the brain secondary to disease 
of the arteries supplying the brain and medulla. This is why a 
patient may show " uremic " attacks even though his kidne} r 
function is perfectly adequate. On the retention basis such an 
apparent inconsistency cannot be explained. The recurrent 
attacks of pulmonary oedema may also be interpreted in these 
vascular cases as local cedemas of the lungs secondary to vascular 
disease of the bronchial arteries. 

It remains to discuss why attacks of " glaucoma," of " ure- 
mia," of pulmonary oedema, etc., are so often periodic in character 
1 See Part Seven, on Glaucoma. 



NEPHRITIS 



633 



instead of persisting after once being established. The reason 
for this resides in the fact that the factors conspiring to pro- 
duce the localized cedemas do not always reside wholly in the 
blood vessels. An involved organ does not betray that it is 
suffering from vascular disease until this has advanced to a point 
where the organ approaches a state of partial oxygen want. 
In consequence of this, it begins to accumulate acids and sim- 
ilarly acting substances and to swell. Slight or no symptoms 
may attend this state, but when the products of hard work, 
of infection, of dietary indiscretion, of alcoholic excess or of 
a heart lesion are added, the involved organ swells more acutely 
and so gives rise to the obvious clinical manifestations with 
which we are familiar. If nature or we succeed in removing 
this added factor the patient may recover from his attack 
to get along until new indiscretions precipitate a second. The 
important difference between the " uremic " attack observed, 
for example, in an eclamptic woman and that observed in a 
man with vascular disease resides not in the attacks themselves 
or in the cedemas of the brain underlying both, but in the mech- 
anism leading to these. In the former case recurrence is not 
to be anticipated after the pregnancy has been brought to a 
close, and the brain cedema has once been reduced, but in the 
second the persistent vascular disease continues to hold the 
patient liable to another attack. 

As familiarly known, the sufferers from chronic interstitial 
nephritis do not show the generalized cedema, the decreased 
urinary output and the large numbers of casts with much albumin 
which distinguish the frankly parenchymatous form. In the 
terminal stages of the disease, however, this picture is frequently 
found. When it occurs our chronic interstitial nephritis has 
given way to a frankly parenchymatous form. Back of this 
change there must lie, as in the frankly parenchymatous forms, 
a general intoxication, and this intoxication, when not due to 
any of the accidents which may overcome the normal individual, 
is most commonly dependent on a failure of the circulation in 
consequence of a dilated heart, a failing heart muscle or defectively 
working sclerosed valves. The oxygen supply of the entire body 
of the patient is thereby diminished, and, as this occurs, all his 
organs begin to develop an cedema. It is for this reason that his 
body tissues generally swell, his liver now shows enlargement 



634 



(EDEMA AND NEPHRITIS 



and the symptoms of a brain oedema gradually supervene. At 
the same time the urinary secretion falls, the casts increase and 
the albumin content rises. In this stage the blood pressure 
may also show signs of falling — a sign alike of the failing cardiac 
efficiency and oncoming death of the individual and a conclusive 
argument against the notion that the high blood pressure was in 
itself either bad for the patient or responsible for his condition. 



5. Remarks on the Etiology of Vascular Disease 



When we make certain types of nephritis secondary to vascular 
disease and the alleged consequences of such nephritides but the 
expression of vascular disease in other organs, it becomes apparent 
that a rational therapy for the whole can hope to rear itself only 
upon what we assume to be the causes of the blood vessel changes. 
As such causes almost everything has been listed, but it is certain 
that many or most of these alleged etiological factors have noth- 
ing to do with the production of the disease. However injurious 
may be the effects of alcohol, coffee, tobacco, hard work, in- 
testinal fermentation, the products of an infectious disease, 
etc., upon a man with an established vascular disease, they have, 
as a matter of fact, nothing to do with its origin. Not only has 
everyone seen individuals who for years have been addicted to 
the abuse of alcohol or have worked excessively, or have been the 
subjects of steady intoxication, and who, nevertheless, show no 
particle of vascular degeneration, but simple study of the lesions 
characteristic of vascular disease is sufficient to indicate that 
no generalized intoxication can lie behind the process. The 
lesions of blood vessel disease are focal in nature, and even when 
the involved spots become so numerous that large portions of 
the blood vessels are involved, goodly portions of healthy blood 
vessels are, nevertheless, always to be discovered in even the most 
advancedly degenerated cases. Such lesions cannot be explained 
on the basis of a general poisoning. Alcohol, the products of hard 
work, the toxins of an infection, a soluble metallic salt or any 
other soluble poison cannot course through the blood vessels 
and pick out only limited areas. Such poisons would involve 
the whole of the media or the whole of the intima of the blood 
vessels, and at once. To get the spotty lesions characteristic of 



NEPHRITIS 



635 



vascular disease we must have a spotty cause. A generalized 
intoxication does not constitute such. 

Through the brilliant clinical studies of Frank Billings 1 
and the bacteriological researches of Edward C. Rosenow 2 we 
have obtained light regarding the origin of such spotty lesions. 
Rosenow has showed that the lesions of endocarditis, of peri- 
carditis, of articular and muscular rheumatism, of certain types 
of gastric ulcer, cholecystitis, appendicitis, and nephritis are in 
essence all the same. Micro-organisms are responsible for these 
pathological entities, producing their initial lesions by collecting 
in clumps in the tiny blood vessels supplying the heart valves, 
the pericardium, the joint surfaces, the tendinous insertions 
of muscles, the gastric mucosa and the kidney. The injury to 
the blood vessels by such bacterial emboli is followed by a 
thickening of the intima and thrombotic changes, the sum 
total of which leads to anemia and oedema of the involved 
part, to be followed all too often by degeneration and destruction. 

The anatomical lesions characteristic of vascular disease are 
identical with those observed by Rosenow in other diseases and must 
have behind them an infectious organism. When vascular disease 
attacks the larger blood vessels the original lesions occur in the 
media. The series of changes (intimal thickening, swelling, 
degeneration) observed here are really consequent upon changes 
involving the vasavasorum, and these changes in the vasa- 
vasorum are identical with similar changes which may be observed 
in any of the smallest blood vessels found elsewhere in the body. 
The primary changes of vascular disease are similar in nature to 
those produced anywhere else in the body when small blood vessels 
become the seat of infectious embolism. The etiological impor- 
tance of the spirochete of syphilis in the production of blood 
vessel disease has long been recognized. What we need to make 
further progress toward a correct understanding of its nature and 
cause is more bacteriological study and less profitless chasing 
of " metabolic " will-o'-the-wisps. 

There are already at hand many suggestive studies which 
indicate the parasitic origin of the initial lesion of vascular 

1 Frank Billings: Arch. Int. Med., 4, 409 (1909); 9, 484, (1912); Jour. 
Am. Med. Assoc., 71, 819 (1913); 63, 11 (1914). 

2 Edward C. Rosenow: See page 815, as well as his various papers of the 
last five years in the Journal of Infectious Diseases and the Journal of the 
American Medical Association. 



636 



(EDEMA AND NEPHRITIS 



disease. Y. Manouelin 1 found that the repeated intravenous 
injection of yellow and white staphylococci killed at 56°, 60° and 
100° C. into rabbits and monkeys for six to nine months resulted 
in the production of atheroma in 84 per cent of rabbits and 
in five out of six monkeys; while T. B. Hartzell and A. T. 
Henrici 2 describe incidentally the observation of vascular changes 
after the intravenous injection of streptococci isolated from alveo- 
lar abscesses. Even when due allowance is made for the " spon- 
taneous" vascular lesions observable in various laboratory animals 
these findings are nevertheless striking. James J. Hogan 3 has 
moreover isolated organisms of the streptococcus group from the 
walls of varicose veins removed surgically while E. R. Le Count 
and Lelia Jackson 4 describe the localization of organisms of 
the streptococcus group in the small arteries of the kidney — the 
very spots in which vascular disease first involves the kidney to 
produce the beginnings of chronic Bright's disease. 

To accept the infectious nature of vascular disease is to 
stimulate a therapeusis which, it seems to me, promises more for 
the patient than the old expectant scheme of treatment. To 
connect vascular disease with a syphilitic infection is to get a 
rational basis for the use of iodids, mercury and other anti- 
syphilitic agencies. Where a syphilitic infection can be elimi- 
nated, attention to infected tonsils, infected teeth, infected ears, 
old genito-urinary and pelvic infections, etc., has, in my opinion, 
yielded better results than our former empirical methods. 

IX 

THE DISTURBANCES IN SECRETION IN NEPHRITIS 
1. General Considerations 

The changes observed in the secretion of urine in any case of 
nephritis fall into two groups: the changes in the amount secreted 
in any unit of time and the changes in the quantitative composi- 
tion of the urine. In all except certain of the so-called chronic 

1 Y. Manouelin: Ann. l'Inst. Pasteur, 27, 12 (1912). 

2 T. B. Hartzell and A. T. Henrici: Jour. Am. Med. Assoc., 64, 1055 
(1915). 

3 James J. Hogan: Personal communication (1913). 

4 E. R. Le Count and Lelia Jackson: Jour. Infectious Dis., 15, 389 
(1914). 



NEPHRITIS 



637 



interstitial types of nephritis the secretion of water is diminished. 
In the chronic interstitial types associated with blood vessel 
disease it is said to be increased. So far as the secretion of dis- 
solved substances in nephritis is concerned, it is generally accepted 
that (diet duly considered!) there exists not only a diminution 
in the total amount of dissolved substances eliminated, but 
variations in the proportion of the dissolved substances when 
compared with other and regarded in the light of the way in which 
these same substances are eliminated during health. What 
happens here is interesting. We find that certain substances 
may be eliminated as well by the diseased kidney as by the 
normal. Certain other substances are eliminated in much smaller 
amounts than is normal, so small, in fact, that it is often said 
not at all. Experiments and observations to indicate that a 
nephritic kidney may secrete yet other substances even" better 
than a normal kidney are not on record so far as I know. Quan- 
tity of urine duly considered, such a thing is theoretically not 
impossible. 1 

It is" generally said that in chronic interstitial nephritis 
associated with vascular disease the secretion of water by the 
patient is not diminished as in the parenchymatous forms, 
but is normal in amount, or, as the majority of clinicians and 
pathologists are wont to say, is increased in amount. 

To the claim that the urinary output is increased, serious 
objection must be made. It is better simply to say that the 
output is normal. Urinary secretion is normal if (with due 
regard to loss of water through skin, lungs, and intestinal tract) 
all the water consumed by an individual is excreted again, as 
urine — that is to say, none is retained (cedema) and not more 
than has been consumed is excreted (abnormal loss). If a man 
consumes only a liter of water a day and secretes a liter of urine 
(skin, etc., being ignored) his urinary secretion is normal, and if 
he consumes twenty liters and secretes twenty it is normal. 
We may differ as to which of these amounts, if either, we consider 
as normal (better optimal) from the standpoint of consumption, 
but so far as secretion is concerned, both are normal. And for 

1 Since this was first written Walter A. Baetjer (Arch. Int. Medicine, 
11, 593 (1913)), has proved that the nephritic kidney secretes certain sub- 
stances better than the normal, and has collected illustrations from the older 
literature which support his own findings. 



638 



(EDEMA AND NEPHRITIS 



this reason I would insist that the patient with chronic interstitial 
nephritis who happens to consume in response to his tastes three 
liters of water and so secretes three liters of urine (skin, etc., again 
ignored) has not an increased urinary output, but a normal one. 

The amount of water consumed by an individual is governed 
by his sense of thirst, which represents in essence a certain degree 
of dryness of some or all of his tissues. Such a dryness tends 
to be increased in a patient with vascular disease. While it 
is true that certain regions in his various organs are through 
the blood vessel disease rendered liable to oedema, the blood 
vessel disease does not affect all the vessels to the same extent 
and so, because of the increased blood pressure, etc., such 
unaffected regions may actually be better supplied with blood 
than normally. They therefore tend to be drier, or in the case 
of the kidney, such non-involved regions would actually secrete 
water better than normally. Hence a tendency to an even better 
than normal water elimination, a greater dryness of the tissues 
generally, a greater thirst, and a greater water consumption. 

The reasons for the normal water output by the patient 
with chronic interstitial nephritis associated with vascular dis- 
ease reside in the fact that he still has large amounts of kidney 
substance acting normally, and as a quarter of his total kidney 
substance easily suffices to yield a normal water output, he 
shows no decrease in this as long as such an amount remains 
available. The nephritic portions of the kidney do not secrete 
water in chronic interstitial nephritis any more than do the 
cells in the generalized parenchymatous case. It is the unin- 
jured cells between the nephritic portions which keep the water out- 
put in a cose of chronic interstitial nephritis up to normal. When 
for any reason enough or all of the remaining portions of still 
functioning kidney in chronic interstitial nephritis become 
involved, then the urinary secretion falls. The claim that water 
secretion is normal (or increased) in chronic interstitial nephritis 
holds only as long as sufficient quantities of normal parenchyma 
remain between the involved areas, 

2. The Secretion of Water by the Nephritic Kidney 

In support of the thesis that an abnormal accumulation 
or production of acid in the kidney constitutes the basic cause 



NEPHRITIS 



639 



of every nephritis, it would be sufficient in this section merely 
to show that such a condition always leads to a decrease in 
the secretion of water by the kidney. We shall, however, not 
stop with this but try to indicate in a little more detail where 
lies the point of attack for the acid that is responsible for such 
a change in secretion. 

It is an easy matter to show that the direct introduction of 
acid into the kidney, or any method capable of leading to an 
abnormal acid content in the kidney, is followed by a decrease 
in urinary secretion which may go to the point of absolute stoppage. 
This is clearly evident in the accompanying drawings, which 
have been constructed from the experiments detailed in various 
divisions of this volume. 

Fig. 201 on page 653 has been introduced to show the nor- 
mal secretion of urine in three rabbits, kept on a mixed diet, 
when these are brought into the laboratory and are loosely tied 
into an animal holder. When the animals are snugly tied into 
a holder, the urinary secretion is decreased in amount. This 
is clear from Fig. 202 in which are shown the curves for the 
urinary secretions obtained in the animals that were rendered 
albuminuric by this means (Experiments 84, 85, 86 and 87). 
If instead of such a general state of lack of oxygen in the body 
we interfere locally with the blood supply to the kidney, as 
through clamping of the renal blood vessels, the same great fall 
in urinary output is observed, as is evidenced in the lowermost 
curve of Fig. 207. But to show that it is really the acid developed 
in the body as a whole, or in the kidney specifically, that under 
these circumstances is responsible for such a fall in secretion, 
it is best to inject the acid directly. The effect of such a pro- 
ceeding is shown in Fig. 205 based on Experiments 59, 60 and 
61. It would be purposeless to multiply these experiments 
to support further the contention that an abnormal acid con- 
tent in the kidney leads to a decrease in the secretion of water. 
As a matter of fact it finds daily corroboration in the decreased 
urinary output observed in all those clinical cases, such as heart 
disease, respiratory disease, etc., which we know to be associated 
with an abnormal accumulation and production of acids in 
the body. 

But how may we imagine the acid to be effective in this regard? 
A proper answer to this question demands a critical review 



640 



(EDEMA AND NEPHRITIS 



of all the various theories that have been proposed from time 
to time to explain the mechanism of normal urinary secretion, 
and this would lead us too far afield. 1 We can, however, help 
toward a more circumscribed formulation of the whole problem. 

Defined physicochemically, the problem of water secre- 
tion by the kidney is essentially the problem of how water 
contained in the blood is made to pass through a solid (hydro- 
philic) colloid membrane, this being represented, in the case 
of the kidney, by the various cells and their intercellular sub- 
stances that he between the blood on the one hand and the urine 
on the other. 

In the light of what has been written in the preceding pages 
and accepting as best supported the theory that water is lost 
from the kidney by a process of filtration, the action of an acid 
or similarly acting substance in inhibiting or suppressing the secre- 
tion of water may be conceived of somewhat as follows: 

(1) The acid acts upon all the tissues of the body^ including the 
blood and lymph. The increased hydration capacity resulting 
from this makes these tissues hold more water in combined form 
(maintenance of body oedema) while at the same time it prevents 
water becoming "free" in the arterial blood stream. A first 
reason for non-secretion of urine is therefore resident in the fact 
that the blood passing through the kidney contains no "free" 
water. 

(2) A second action of the acid is upon the colloids of the kidney 
themselves. The consequence of this is again swelling of the kid- 
ney substance or, in the terms of secretion, a swelling of the filtra- 
tion membrane through which "free" water alone can pass under 
normal circumstances. Such swelling closes the pores of the filter 
so that even when "free" water is brought to the kidney it cannot 
be given passage. The process is, in other words, analogous to 
failure of the hydrophilic colloid membranes (like sodium stearate) 
to give passage to water under a given hydrostatic pressure when- 
ever the porosity of such a colloid membrane is reduced. 

3. The Secretion of Dissolved Substances by the Nephritic Kidney 

As already noted, the nephritic kidney shows deviations 
from the normal secretion of dissolved substances by it in two 
directions. Other conditions remaining the same there is, first, 

1 See the previous sections on urinary secretion beginning on page 325. 



NEPHRITIS 



641 



a decrease in the absolute amounts of the various substances 
secreted, and second, a change in the relative proportions that 
these bear to each other when compared with the secretion 
of these same substances as observed in health. The nephritic 
kidney secretes some substances as well as does the healthy 
kidney, others decidedly less well, a third group even better. 1 It 
is our problem to say how such a condition as an acid produc- 
tion in the kidney brings this state of affairs to pass. In 
order to do this we must recall some of the facts of normal secre- 
tion by the kidney. 

As is familiar to everyone, a secretion of some substances 
proportionately more easily than others, in other words, a 
" selective " secretion by the kidney, is not characteristic of the 
diseased kidney, but of the healthy kidney as well. This is 
really the rock on which most of the mechanical, or to use a 
broader and better term, non-vitalistic or physico-chemical 
conceptions of urinary secretion have foundered — and these 
founderings have given momentary comfort to those who 
believe that kidney secretion, as many another physiological 
phenomenon, is " vital " in character. But such a pessimism 
would seem to be premature, for we are already familiar in 
physical chemistry with not a few systems in which differences 
in the concentration of any substance are easily maintained over 
indefinitely long periods of time, and, of course, without the 
assistance of those " peculiar " forces believed by some to 
inhabit the living cell. Reference is here made to the difference 
in the distribution of any substance between two phases (the distri- 
bution coefficient. 2 

Through the work of Hans Meyer and E. Overton the 
differences in the solubility of such substances as alcohol, 
ether, chloroform, morphin, cocain, etc., in water and in fats 
and fatlike bodies (lipoids) — their distribution coefficients be- 
tween two solvents — have been shown to explain very satis- 
factorily why these substances not only diffuse with greater speed 
into and through cells, especially rich in the fatlike bodies (the 
fat cells and the cells of the central nervous system), than into 
and through such as contain these in smaller amounts (yellow 
elastic tissue, white fibrous tissue), but why in the end they are 
found in larger absolute amounts in some tissues than in others. 

*See W. A. Baetjer: Arch. Int. Med., 11, 593 (1913). 
2 See page 207. 



642 



OEDEMA AND NEPHRITIS 



A second property of protoplasm which permits one cell 
or tissue to take up more of any given substance, and this 
more speedily than is the case with another cell, is the char- 
acter of the colloids contained in the cells and their state. This 
is one of the reasons why certain stains when injected intraven- 
ously are not taken up with the same speed, or to the same ex- 
tent, by all the tissues of the body. 

A third property of protoplasm, which makes for inequal- 
ities in the distribution of a substance, resides in the chemical 
differences existing between different kinds of protoplasm. 
Certain, but by no means all, of the " vital " and " specific " 
protoplasmic stains are examples of this class. In these a chem- 
ical combination results between the dye and the chemical 
compounds found in some cells. 

What use can we make of these facts in the explanation of the 
alterations observed in the secretion of dissolved substances 
by the nephritic kidney? In discussing the colloid-chemical 
theory of urinary secretion, 1 I tried to show how the " selective " 
character of secretion may be explained in the following way: 

All secretion of dissolved material by the kidmy is dependent 
upon a primary secretion of water by the kidney. After the water 
is secreted all the constituents which characterize it as urine come 
to be added to it, in its course through the uriniferous tubules, 
by a process of leaching out of the dissolved substances present 
in the kidney cells. But in this process of leaching out, not 
all the constituents present in the protoplasm leave the cells 
in which they are originally present with the same ease. Depend- 
ing upon the character of the dissolved substance, and the state 
of the protoplasm as to lipoid content, colloid state, and chemical 
composition, the water present in the uriniferous tubule may 
come to take up the dissolved substance to an extent which allows 
it ultimately to be found here in a lower concentration than in 
the kidney cells, in the same concentration, or in a greater one. 
It is all a matter of equilibrium. But the equilibrium points 
with different substances are different, and so the relative 
amounts of these different substances that appear in the urine 
are also different. In other words, the (normal) leaching out 
is " selective," or, to put it biologically, the " secretion " of 
the dissolved substances is selective. 

But this leaching out of dissolved substances from the kidney 
1 See page 367. 



NEPHRITIS 



643 



is only one- half of the process of urinary secretion. The other 
half is the process of the absorption of dissolved substances from 
the blood by the kidney cells preparatory to their secretion 
into the lumen of the uriniferous tubules. This is also a selective 
process, and here the same laws of lipoid solubility, colloid 
adsorption, and chemical combination, which have already been 
discussed in the leaching out process, again come into play. 

All these various processes of absorption and secretion of 
dissolved substances by the kidney cells are most markedly influenced 
by the content of acid, of salts, etc., in them, and it is for this reason 
that the observed variations from the normal in the secretion of 
dissolved substances by the nephritic kidney occur. 

It is easily appreciated why there must be, a decrease in 
the absolute amount of dissolved substance secreted by the 
nephritic kidney. If the secretion of water is diminished, then 
not as much dissolved substance can be leached out of the kid- 
ney parenchyma as when more is secreted. Into this, however, 
enters the element of time. When much water is being secreted 
by a kidney its discharge into the pelvis of the kidney is also 
hastened. The time that a given portion of the urine (secreted 
as water initially) is in contact with the kidney cells is thereby 
diminished, and so not all that this water is capable of absorbing 
is taken up. When the water is secreted more slowly, the ultimate 
equilibrium point for the distribution of dissolved substances 
between the kidney and the urine is more nearly approximated. 
We find daily expression of this in the clinical observation that 
after the consumption of much water the concentration of the 
urine falls, while with a diminished intake of water, or when 
the kidney cannot secrete it (as in nephritis), the concentration 
of the urine becomes progressively higher. Yet, other things 
being equal, the absolute amount of any dissolved substance 
secreted by the kidney must be the greater, the larger the absolute 
amount of water secreted by the kidney in any unit of time. 

To illustrate how the increased acid content in the kidney 
in nephritis leads to variations - in the secretion of the dissolved 
substances, I introduce some simple test-tube experiments 
and experiments on rabbits, which concern themselves particularly 
with that part of the selective secretion which deals with the 
state of the colloids in the kidney cells. This constitutes by 
far the most important part of the whole problem of selective 
absorption and secretion, for the state of a colloid in the body 



644 



(EDEMA AND NEPHRITIS 



is more easily affected by external conditions than is the solvent 
property of a lipoid, or the chemical character of any part of 
living protoplasm. As the various dyes betray themselves 
not only qualitatively, but, in a sense, also quantitatively, 
to the naked eye, illustrations of the " absorption " and the 
" secretion " of these, under conditions that interest us in our 
discussion of nephritis, seemed to me best suited to our needs. 
I chose, moreover, dyes that have been used physiologically 
in the study of the kidney. The results of a few experiments 
on the staining of fibrin, which are familiar to any worker who 
has at all touched upon the problem of dyeing, and which might 
be multiplied indefinitely by using other dyes and different 
colloids, are shown in Fig. 200. 

Tube 1 contains an aqueous solution of toluidin blue. If 
into another tube (2) , .containing the dye in the same concentra- 
tion, some powdered fibrin is dropped, this soon absorbs most 
of the dye and stains intensely blue. The supernatant liquid 
retains only a faint tinge of the blue, but this remains indefinitely. 
If the supernatant solution is carefully pipetted off, and distilled 
water is placed over the dyed fibrin, the water now slowly turns 
blue. In this way, through successive washings, we can again 
get considerable of the blue out of the fibrin. In other words, 
the fibrin absorbs the dye until an equilibrium is reached 
between the concentration of the dye in the fibrin and the 
concentration of the dye dissolved in the supernatant liquid. 
If we disturb this equilibrium by removing the blue solu- 
tion above the fibrin and substituting water for it, some of the 
dye comes out of the fibrin until equilibrium is once more 
established. 

If we will now substitute the words kidney colloids for fibrin 
we have what happens in the kidney when it secretes any dye. 
The absorption of the dye by it from the blood is analogous 
to the first series of changes, the leaching out of the dye by the 
urine to the second. We see also why the quantity of urine 
secreted and the time that this remains in contact with the 
kidney cells are of such importance. This corresponds with 
the renewal of the distilled water above the dyed fibrin and the 
time this is allowed to remain there before being pipetted off. 

What happens if we introduce into this whole system a 
trace of acid? The result is shown in tube 3. The fibrin swells 
somewhat, but the toluidin blue is now scarcely taken up. The 



NEPHRITIS 



645 



supernatant liquid remains practically as blue as the control 
tube 1. What would this mean when applied to the kidney 
affected with nephritis, for which we have maintained that an 
abnormal acid content is responsible? That the kidney would 
swell as does the fibrin, we already know. But such a kidney 
would now not absorb the toluidin blue preparatory for secre- 
tion as does the healthy kidney. Yet, we must not hastily 
conclude herefrom that under such - circumstances the kidney 
would necessarily secrete this dye badly. Once any dye was 
in the kidney colloids it would rapidly diffuse into the urine, 
not only because the kidney colloids are not holding on to the dye 
particularly firmly, but because the acid liable to be in such urine 
as is secreted from the nephritic kidney would further favor the 
passage of the dye into it. 

In tubes 4, 5, and 6 are shown a parallel series of experi- 
ments carried out with sodium indigosulphonate. It is clear 
that with this dye conditions are exactly the reverse of those 
obtaining in the case of toluidin blue. The very circumstances 
which favor absorption before, hinder it here, and those which 
hindered it before now favor it. In tubes 7, 8, and 9 are shown 
the results obtainable with neutral red, which, it will be observed, 
behaves like toluidin blue. 

But the kidney is not thus offered one substance at a time 
to secrete into the urine. The blood that passes through this 
organ brings it many at once. What must be the behavior 
of the tissue colloids under such circumstances? As tubes 
10, 11, and 12, and tubes 13, 14, and 15 clearly show, a colloid 
under such circumstances behaves toward each of the substances 
offered it as though the others were not present. In tube 10 
is shown the effect of mixing sodium indigosulphonate and 
neutral red. If some fibrin is introduced into this mixture it 
absorbs the red (chiefly) and leaves behind (almost) all the blue. 
This would correspond with the kidney function in health. If 
now an abnormal amount of acid were present in the kidney 
(nephritis) just the reverse would result — the red would now be 
left behind in the blood, while the blue would be absorbed. 

In tubes 13, 14, and 15 are shown the results on the stain- 
ing of fibrin when toluidin blue and neutral red are mixed. 
The resulting color is shown in tube 13. In the presence of 
fibrin alone both of the dyes are absorbed as shown in tube 14, 
but if a little acid is present, or is subsequently added, the fibrin 



646 (EDEMA AND NEPHRITIS 

fails to stain. Fig. 200 was painted from the results obtained 
in Experiment 83, after the tubes had stood some eighteen hours. 
Marked differences in the degree of staining are readily visible, 
however, after ten minutes. 

Experiment 83. 

1. 15 cc. .01% toluidin blue+15 cc. water. 

2. 15 cc. .01% toluidin blue+15 cc. water+0.4 gram fibrin. 

3. 15 cc. .01% toluidin blue+15 cc. n/20 acetic acid+0.4 gram 
fibrin. 

4. 15 cc. .02% sodium indigosulphonate+15 cc. water. 

5. 15 cc. .02% sodium indigosulphonate+15 cc. water+0.4 gram 
fibrin. 

6. 15 cc. .02% sodium indigosulphonate + 15 cc. n/20 acetic acid+0.4 
gram fibrin. 

7. 15 cc. .02% neutral red+15 cc. water. 

8. 15 cc. .02% neutral red+15 cc. water+0.4 gram fibrin. 

9. 15 cc. .02% neutral red+15 cc. n/20 acetic acid+0.4 gram fibrin. 

10. 15 cc. .02% sodium indigosulphonate+15 cc. .02% neutral red. 

11. 15 cc. .02% sodium indigosulphonate+15 cc. .02% neutral red 
+0.4 gram fibrin. 

12. 7| cc. .04% sodium indigosulphonate+7| cc. .04% neutral red 
+ 15 cc. n/20 acetic acid+0.4 gram fibrin. 

13. 15 cc. .01% toluidin blue+15 cc. .02% neutral red. 

14. 15 cc. .01% toluidin blue+15 cc. .02% neutral red+0.4 gram 
fibrin. 

15. 1\ cc. .02% toluidin blue+7| cc. .04% neutral red+15 cc. n/20 
acetic acid+0.4 gram fibrin. 

The details of this experiment have already been discussed in the 
text. 

It follows from all this that the presence of a little acid 
in such colloid material as composes the kidney must be followed 
by profound changes in the character of the secretion of dis- 
solved substances by it as compared with the normal secretion 
of these same substances. But depending upon the way in which 
the acid displaces the equilibrium point, it is clear that, with 
otherwise constant conditions, the secretion of any substance 
may not only be decreased or simply remain unaffected, but it 
may actually be increased. 

Before closing this chapter it is well to refer to a few animal 
experiments which show that what has been said above regard- 
ing the staining of fibrin actually holds in the case of the living 
animal. As pointed out in our discussion of the experiments 
of Heidenhain, Dreser, and Nussbaum, these authors found 



NEPHRITIS 



647 



the kidneys of their experimental animals stained most 
deeply, and most generally, with sodium indigosulphonate or 
acid fuchsin (which stains fibrin just as does sodium indigo- 
sulphonate) when conditions favoring the accumulation of acid 
in the kidney were most clearly at hand. This corresponds 
with the improved tendency of fibrin to stain with these dyes 
when an acid is present. When in a rabbit under morphin anes- 
thesia the artery to one kidney is clamped for an hour or two, 
and the clamp is then removed while sodium indigosulphonate 
or acid fuchsin is injected intravenously, it is found that the 
clamped kidney not only stains sooner than the undamped one, 
but more intensely. When frozen sections are made of the two 
kidneys the dye in the healthy kidney is found only in the lumina 
of the uriniferous tubules, while in the ligated one it is found 
in the cells themselves. And yet a kidney so clamped for 
an hour or two may not yield any urine for hours afterwards. 
Mere staining of the kidney, as already noted above, can not at 
once be taken as an index of secretion. 

The reverse of this experiment can be done with neutral 
red. Here the normal kidney stains well and rapidly, while 
the clamped one remains without color, owing to the acid developed 
in it in the absence of a circulation. 

After what has been said it must be self-evident that so 
many factors enter into the picture of the secretion of any 
dissolved substance by the kidney — so many at which we can 
to-day but guess in a clinical case — that conclusions regard- 
ing the functional activity of the kidney, as derived from a 
study of the elimination of some one compound swallowed by 
or injected into the patient and sought for in his urine, must 
only be drawn with the greatest care. Even though we ignore 
all other elements of error, the state of the blood, the state of 
the kidney colloids, and the state of the urine all influence 
the rapidity and perfection of the elimination of the substance 
in so marked and (for us) uncontrollable a way, that trust- 
worthy conclusions are hardly possible, and when we take the 
liberty, as is so often done, of applying without modification 
what we may have learned from the elimination of one sub- 
stance to some other or all other constituents found in the urine, 
then we are on dangerous ground indeed. Until we have learned 
far more regarding the laws that govern the secretion of dissolved 
substances by the kidney than we know to-day, we had best 



648 



(EDEMA AND NEPHRITIS 



accept as the most reliable test for the functional activity of this 
organ its ability to eliminate water. 1 

X 

SOME EXPERIMENTAL FOUNDATIONS FOR THE TREAT- 
MENT OF NEPHRITIS. FALLACY OF SALT RESTRIC- 
TION IN NEPHRITIS AND (EDEMA 

1. Introduction 

Before use is made in clinical practice of the rather obvious 
conclusions to which the considerations of the previous pages 
compel us, conservatism demands that we apply a further 
test to them. We have labored thus far to show how a parallelism 
exists between the changes that various protein colloids undergo 
in the presence of acid and similarly acting substances, and the 
changes that are observed in the kidney when this becomes 
the seat of a nephritis. We have noted how the swelling of the 
kidney in nephritis is like the swelling of fibrin or gelatin in water 
when a little acid is added to this; how under the same circum- 
stances some of the colloids go into solution, and so the develop- 
ment of an albuminuria is simulated; how when a colloid of the 
nature of casein is mixed with these, it is precipitated under 
conditions which make the others swell, thus behaving like cer- 
tain granules observed to arise in the cells of the kidney under 
conditions associated with a nephritis. 

In studying the behavior of the pure colloids we learned 
more than this. We learned that the swelling of the colloids 
could be reduced, not only by neutralizing the acid, but by add- 
ing to the acid any neutral salt. So far as the precipitation 
of^casein was concerned the salts divided themselves into two 
groups — the one added itself to the effect of the acid and favored 
precipitation, the other counteracted such an effect. If now our 
contention is correct that the series of changes observed in these 
simple colloids and in the kidney are identical in character, then 
it is to be expected that the administration of properly selected 
salts should relieve- the various signs characteristic of a nephritis. 

1 See page 757. 



NEPHRITIS 



649 



That such is the case is not only a long accepted clinical fact, 
but can easily be proved experimentally. 

Of the many salts which might be tested one can, of course, 
foresee that those will give best results which have no " specific " 
poisonous action, which have the power of neutralizing acid, 
and which combine a maximum of those effects which tend on 
the whole to help the nephritis (reduction of protein solubility 
and swelling of the kidney) with a minimum of those which 
aggravate such a condition (augmentation of protein precipita- 
tion in the cells). But neutral salts are also effective in reduc- 
ing the solution and the swelling of such colloids as fibrin, gelatin 
and serum albumin. Of the long list of such, one has in recent 
years been particularly signaled out for attack. It has been 
widely taught that sodium chlorid is not only not good for a 
nephritic, but distinctly bad, in that it is held to increase not 
only the signs of a nephritis, but is supposed to be responsible for 
a retention of water and so for the aggravation of the cedemas 
so often seen accompanying such. Neither in the observations 
on pure proteins nor in the experiments on urinary secretion can 
a single fact be found to support such a view. As the following 
experiments show, various neutral salts decrease the signs and 
symptoms of nephritis, and sodium chlorid is no exception to this 
rule. 

In order to show that salts inhibit the development of the 
signs of a nephritis, it was first necessary to decide upon satis- 
factory methods of producing a nephritis experimentally in 
animals, upon which might then be tried the action of various 
salts. Three different ones were employed : interference with the 
respiration of the animal, the intravenous injection of acid, 
and direct clamping of the renal blood vessels. Of all these 
the last named is probably grossest in its effects upon the kidney. 
For the sake of comparison the protocols of the experiments 
on the animals which served as controls have been inserted in 
each case. 

2. Asphyxial Nephritis 

Let us first consider the nephritis that develops in rabbits, 
when these are tied into the animal holder sufficiently tightly to 
interfere with their respiration. One always gets an albuminuria 
after such a procedure, as Experiments, 84, 85, 86 and 87 show. 



650 



(EDEMA AND NEPHRITIS 



Experiment 84. — White rabbit; weight 898 grams. Fed wheat 
and grass. Snugly tied into holder. Urine obtained with soft rubber 
catheter. 



Urine in cc. 



Remarks. 



3.7 
5.0 
3.0 
1.8 
0.9 
1.1 
1.5 
1.8 



Bound into holder. 

Alkaline to litmus paper. No albumin. 

Clearer urine. Neutral to litmus paper. Trace of albumin. 
Clear urine. Neutral to litmus. Albumin present. 

Clear. Neutral to litmus. Albumin present in every sample, 

and increasing in amount. 



Animal seems entirely well. Returned to hutch. 



Experiment 85. — Belgian hare; weight 1226 grams. Fed wheat 
and grass. Snugly tied into holder. Urine obtained with a soft rubber 
catheter. 



Time. 


Urine in cc. 


Remarks. 


2 


45 


Few drops "> 




3 
3 


00 
15 


1.0 

0.5 | 


Alkaline, thick, chrome yellow. No albumin.. 


3 


30 


Few drops J 




3 


45 


Few drops 


Neutral and clearer. Trace of albumin. 


4 


00 


Few drops -\ 




4 


15 


Few drops 




4 


45 


2.0 f 


Neutral and clearer. Albumin present in every sample. 


5 


00 


Few drops 




5 


15 


Few drops -* 




5 


16 




Animal released and returned to hutch. 



Experiment 86. — Belgian hare; weight 1020 grams. Fed wheat 
and grass. Snugly tied into animal holder. Urine obtained with a 
soft rubber catheter. 



Time. 


Urine in cc. 


3 


30 


3.0 1 


3 


45 


0.7 


4 


00 


0.5 [ 


4 


15 


Few drops > 


4 


30 


2.4 


4 


45 


8.5 


5 


00 


4.0 -J 


5 


15 


2.0 


5 


30 


Few drops > 


5 


45 


Few drops 


6 


00 


3.0 J 



Remarks. 



Tied down. Turbid, dark yellow. Alkaline to litmus. No 
albumin. 

Turbid, dark yellow, alkaline to litmus. No albumin. 
Clearer, pale yellow. Acid to phenolphthalein. Albumin 
present. 



Clear, acid to phenolphthalein. Albumin present in every 
sample. 



NEPHRITIS 



651 



Experiment 87.— Belgian hare; weight 1100 grams. Fed wheat 
and grass. Snugly tied into holder. Urine obtained with a soft rubber 
catheter. 



Time. 


Urine in cc. 


Remarks. 


4.00 
4.15 
4.30 
4.45 
5.00 
5.15 
5.30 
5.45 
5.46 


1.0 1 
2.0 1 
Few drops f 
1.5 J 
2.0 i 
1.5 

2.5 f 
3.0 J 


Tied down. Alkaline, turbid, thick. No albumin. 

Urine clear, acid to litmus. Albumin present in evory sample. 
Liberated. Returned to cage. 





When, now, rabbits are treated from an experimental stand- 
point in an identical way but have a concentrated salt solution 
injected intravenously, the albuminuria does not develop. This 
is shown by Experiments 88 and 89. 



Experiment 88. — Black rabbit; weight 917 grams. Fed wheat 
and grass. Snugly tied into animal holder. Urine obtained with 
a soft rubber catheter. 105 cc. m/2 (2.918%) NaCl solution are 
given intravenously in the course of the experiment at the rate of 5 cc. 
every five minutes. 



Time. 


Urine in cc. 


Remarks. 


4.00 


7.5 


Thick chrome yellow, alkaline. No albumin. Injection begun. 


4.15 


2.5 


Thick, chrome yellow, alkaline. No albumin. 


4.30 


7.5 


Clearer. No albumin. 


4.45 


12-0 (?)^ 




5.00 


23.0 


Clear as water. Neutral to. litmus. No albumin in any speci- 


5.15 


36.5 \ 


men. 


5.30 


32.0 




5.45 


27.5 J 




5.46 




Animal well. Released and killed by blow on head. Nothing 






abnormal noted on autopsy. 



Experiment 89. — Belgian hare; weight 919 grams. Fed wheat and 
grass. Snugly tied into holder. Urine obtained with a soft rubber cathe- 
ter. 105 cc. m/2 (2.918%) NaCl solution are injected intravenously in 
the course of the experiment at the rate of 5 cc. every five minutes. 



Time. 


Urine in cc. 


Remarks. 


3.15 


4.0 


Alkaline to litmus, thick, yellow. No albumin. 






Injection begun. 


* 3.30 


2.5 


Somewhat clearer. No albumin. 


3.45 


20.0 ] 






4.00 


57.5 






4.15 


40.0 




Clear, colorless. Neutral 'to litmus. No albumin in any 


4.30 


39.0 




specimen. 


4.45 


29.0 






5.00 


37.0 J 







652 (EDEMA AND NEPHRITIS 

s 

The following Experiments 90, 91 and 92 show that a mixture 
of different neutral salts, as represented by a Ringer solution, 
yields entirely similar results. 

Experiment 90. — Belgian hare; weight 901 grams. Fed wheat 
and grass. Snugly tied into holder. Urine obtained with a soft 
rubber catheter. In the course of the experiment there are injected 
intravenously 135 cc. of a Ringer solution X 4, 1 at the rate of 5 cc. 
every five minutes. 



Time. 


Urine in cc. 


Remarks. 


1.4(3 


4.0 


Turbid, alkaline to litmus. No albumin. 


1.45 




Injection into ear begun. 


2.00 


4.0 


Turbid, alkaline to litmus. No albumin. 


2.15 


16.0 . -J 




2.30' 


38.0 




2.45 


47.0 } 


Clear, alkaline. No albumin in any specimen. 


3.00 


40.5 i 




3.15 


32.0 J 




3.30 


13.0 ] 




3.45 


7.0 


Clear, neutral. No albumin in any specimen. 


4.00 


6.0 J 




4.05 


No urine 


Animal well. Returned to cage. 



Experiment 91. — Belgian hare; weight 823 grams. Fed wheat 
and grass. Tied tightly into holder. Urine obtained with a soft 
rubber catheter. In the course of the experiment there are injected 
intravenously 125 cc. of a Ringer solution X4, at the rate of 5 cc. every 
five minutes. 



Time. 


Urine 


in cc. 


Remarks. 


1.50 






Tied down. 


1.55 






Injection into ear begun. 


2.10 








2.25 


3 





Turbid, alkaline. No albumin 


2.40 


18 





Clear, alkaline. No albumin. 


2.55 


13 


° 1 




3.10 
3. .25 


17 
20 




Clear, neutral to litmus. No albumin in any 


3.40 


8 




specimen. 


3.55 


4 


o J 




4.00 






Dies. Nothing abnormal noted at autopsy. 



1 The sodium, potassium, calcium chlorid mixtures that are known as 
Ringer solutions have a different composition with different authors. I 
used the following: NaCl 0.7, CaCl 2 0.0026, KC1 0.035, and H 2 enough to 
make 100 cc. Ringer solution X4 means four times this amount of salts 
in each 100 cc, a solution which has then about the same osmotic concen- 
tration as m/2 NaCl, as used in the previous experiments. 



NEPHRITIS 



653 



Experiment 92. — Belgian hare; weight 855 grams. Fed wheat 
and grass. Tied tightly into holder. Urine obtained with a soft 
rubber catheter. In the course of the experiment there are injected 
intravenously 150 cc. of a Ringer solution X4, at the rate of 5 cc. every 
five minutes. 



Time. 




Remarks. 



2.30 

2.45 
3.00 
3.15 
3.30 
3.45 
4.00 
4.15 
4.30 
4.45 
5.00 
5.15 

5.20 



Turbid, alkaline. No albumin. Tied down and 
intravenous injections into ear begun. 



Urine clears until it looks like water. No albumin 
at any time. 



Clear, acid. No albumin at any time. 

Killed. On autopsy nothing abnormal except that 
25 cc. fluid are obtained from the peritoneal 
cavity! 



Let us now retrace our steps and see what has happened so 
far as urinary secretion is concerned, for we were rather par- 
ticular to emphasize that the ability of a kidney to secrete water 
was the best index of its functional activity. The experiments 
detailed above already suffice to show that the secretion of urine 




Hours 



Figure 201, 



from a nephritic kidney, or one threatened with a nephritis, tends 
to be maintained at a normal level or to be increased by the giving 
of various neutral salts, including sodium chlorid. We need but 
compare with each other the secretion curves of Figs. 202, 203 
and 204 made by plotting time on the horizontal and the number 
of cubic centimeters secreted every fifteen minutes on the vertical 
and Experiments 84 to 92, upon which the curves are based. 
All the figures are drawn to the same scale. 



654 



(EDEMA AND NEPHRITIS 




Hours 



Figure 202. 



Fig. 201 is introduced 
for comparison and shows 
normal urinary secretion 
in three rabbits loosely tied 
into an animal holder. The 
curves a, b, c, and d, of Fig. 
202 (based respectively on 
Experiments 84, 85, 86, 
and 87) show, when compared with the curves of Fig. 201 how 
the secretion of urine is diminished when instead of being loosely 
tied into the animal holder 
the rabbits are so snugly 
tied down as to embarrass 
their respiration. The di- 
minished secretion gives way 
to an enormously heightened 
one if animals similarly 
treated are injected with a 
concentrated sodium chlorid 
solution. Fig. 203 shows 
this. Curve a is taken 
from Experiment 89, curve 
b from Experiment 88. 
These experiments (as 
others to be described di- 
rectly) show clearly that 
administration of sodium 
chlorid does not lead to a 
retention of water by the 
living animal. 

Fig. 204 shows the 
curves obtained by inject- 
ing concentrated Ringer 
solution. Evidently all 
neutral salts (that have not 
specific poisonous effects) 
when injected in sufficient 
concentration increase the 
output of urine. The 

7 , Hours 1 2 

curves a, o and c are con- Figure 203 




NEPHRITIS 



655 



structed respectively from Experiments 90, 91 and 92. These 
rabbits were again snugly tied into animal holders, but not 
only did none of them develop an albuminuria, but in conse- 




Hours 1 2 
Figure 204. 



quence of the injection of concentrated Ringer solution the urinary 
output was greatly increased in all. 



3. Nephritis Produced by Injecting Acid 

As the following experiment shows, sodium chlorid when injected 
intravenously, in concentrated solution, simultaneously with a hydro- 
chloric acid solution of a concentration found in Experiments 60 and 
61 (pages 491 and 492), to lead to the symptoms of a most intense 



656 



(EDEMA AND NEPHRITIS 



nephritis, practically suppresses this. The albuminuria scarcely 
appears, and there are no casts, no red blood corpuscles, no hemo- 
globinuria, no decrease in the amount of urinary secretion, and no 
general oedema. 

Experiment 93. — Belgian hare; weight 2136 grams. Has been 
fed hay, oats, corn, and greens. In the course of the experiment there 
are injected intravenously at a uniform rate 140 cc. of the following 
mixture: 150 cc. n/10 HC1 + 4.666 grams sodium chlorid and 
enough water to make the whole up to 160 cc. This yields a final 
solution, that is m/2 (2.918%) so far as the sodium chlorid is con- 
cerned. Urine obtained with a catheter. 



Time. 


Urine in cc. 


Remarks. 


3.30 






Fastened into animal holder. Catheterized. 


3.45 






Injection into ear begun. 


4.00 





3 


Slightly turbid, neutral to litmus paper. No albumin. No 

casts. 


4.15 


17 





Clear as water, barely reddens blue litmus paper. No albu- 
min. No casts. 


4.30 


61 





Clear, barely affects blue litmus paper. Faint shimmer of 
albumin! No casts! 


4.45 


64 




Urine clear, barely affects blue litmus paper. Faint trace of 


5.00 


58 


l I 


albumin. No casts. No hemoglobinuria at any time. 


5.15 


38 


o 1 


No red blood corpuscles. 


5.18 


1 





Dies. 



Total amount of urine secreted since beginning injection 239.8 cc. 

Autopsy. — Weight 2035 grams! Nothing abnormal is noted. The 
body cavities contain no fluid. The blood seems to coagulate abnormally 
rapidly. 



It might be insisted in criticism of this experiment, that 
while sodium chlorid is thus able to counteract the effects of 
an acid in producing a nephritis, it cannot relieve such after 
once being established. This criticism is met in Experiment 
94, in which a nephritis is first induced by injecting (practically) 
pure acid, after which its relief is brought about by injecting 
m/2 (2.918 per cent) sodium chlorid. 

Experiment 94. — Belgian hare; weight 2343 grams. Fed hay, 
oats, corn and greens. Urine obtained with a soft rubber catheter. 
In the course of the first 1| hours of the experiment there are injected 
at a uniform rate 125 cc. of the following mixture: 120 cc. n/10 HC1 
plus 8 cc. 2/m NaCl, in consequence of which all the signs of a 
nephritis develop. For the acid mixture is then substituted a pure 
m/2 (2.918%) NaCl solution of which, up to the end of the experiment, 
there are injected 125 cc. With the change in the character of the injec- 
tion fluid the signs of the nephritis are seen to disappear. 



NEPHRITIS 657 



Time. 


Urine in cc. 


Remarks. 


2. 


45 


5 





Catheterized. Turbid, light yellow, faintly alkaline to litmus 
paper. No albumin. 'No casts. 


3. 


00 


1 


5 


Weighed. Tied to animal holder. Intravenous injection of 
acid mixture into ear begun. Urine turbid, light yellow, 
faintly alkaline to litmus paper. No albumin. No casts. 


3 


15 


n 
U 


i 


Urine neutral to litmus paper. No albumin. No casts. 


3 


30 








3 


45 


2 


I 


Urine neutral to litmus paper. No albumin. No casts. 


4.00 


10 





Urine faintly acid. Albumin. Isolated casts. Epithelial 










cells and red blood corpuscles. 


4 


15 


7 





Urine has a pink tinge. More albumin. Numerous casta 
and a larger number of red blood corpuscles. Injection of 
acid mixture stopped. Injection of m/2 NaCl begun. 


4 


30 


20 





Urine decidedly red (hemoglobinuria). Albumin content 
still rising. Fewer casts and red blood corpuscles. 


4 


45 


42 





Pink color to urine. Albumin decreasing. No casts can be 
found after long search of sedimented urine. 


5 


00 


60 





Pale pink. Albumin decreasing. No casts or red blood 
corpuscles. 


5 


15 


53 





Like water. Barely visible trace of albumin. No casts or 
blood corpuscles. 


5 


30 


32 





Like water and neutral to litmus paper. No albumin. No 
casts. No blood cells. Injection stopped, as animal has 
embarrassed respiration. 


5 


35 


11 


(?) 


Some urine accidentally lost as animal dies. No albumin. 
No casts. No blood cells. 



Autopsy. — Weight 2342 grams. Nothing abnormal in any of the 
organs. The peritoneal cavity is wetter than normal. The pericar- 
dial and pleural cavities are empty. 



A number of interesting facts come to light in the two 
experiments just detailed. Let us first ask about the out- 
put of urine. In Fig. 205 we find in the curves a and b (Experi- 
ments 60 and 61) a graphic representation of the amount of 
urine secreted when n/10 hydrochloric acid (in m/8, that is, 
0.729 per cent sodium 



chlorid, added to reduce 
somewhat the hemolytic 
action of the acid) is 
injected intravenously. 
When we compare these 
curves with those of Fig. 




201 (normal secretion in Figure 205. 

rabbits), we notice that 

in spite of the great injection of water, the urinary output lies 
below the normal. The presence of the acid along with the water 
brings it to pass that the water is retained in the body; in other 
words, an oedema develops. The same factor, therefore, which we 
are holding responsible for certain of the kidney changes in neph- 



658 



(EDEMA AND NEPHRITIS 



50 



40 



ritis, is responsible for one of the most prominent symptoms of 
such kidney disease, namely, the oedema. 

How enormously the urinary output is increased if a con- 
centrated sodium chlorid solution is 
injected along with the hydrochloric 
acid is apparent when Fig. 206, 
drawn to the same scale, is compared 
with Fig. 205. And when we look 
through the protocols we find that 
this increased urinary output is asso- 
ciated with a loss of weight by the 
animal, in other words, a failure to 
develop an oedema, or the reduction 
or total disappearance of such as 
may be existing. Clearly, therefore, 
salts, including sodium chlorid, all 
tend to reduce ozdema, as I have 
previously insisted. 

Another point of interest in these 
two experiments is the fact that when 
enough sodium chlorid is injected 
along with the acid, the hemoglobi- 
nuria fails to develop. As is well 
known, a pure acid solution when 
injected intravenously leads to a 
rapid and extensive destruction of 
the red blood corpuscles (hemolysis) 
and the escape of hemoglobin in the 
urine. The only reason why some 
sodium chlorid was given along with 
the acid injections in the various ex- 
periments described in this volume, 
in which the effects of the pure acid 
on the kidney were particu- 

if larly sought, was to escape in 

part this so great dissolution 
of the red blood corpuscles. 
When enough sodium chlorid is added the hemolytic action of 
the acid is avoided altogether, as Experiment 93 shows. This 
fact is of interest and importance, not only because it teaches 



20 



10 



cc. 




Hours 



Figure 206. 



NEPHRITIS 



659 



us that by increasing the salts in the diet we can relieve the 
signs and symptoms of paroxysmal hemoglobinuria/ but because 
it was a result to be expected if a theory of hemolysis which I 
have previously advanced 2 should be correct. 

Incidentally, the last two experiments in conjunction with 
Experiments 59, 60 and 61 (pages 490 to 492) serve to meet a 
criticism that might have been raised against the experiments 
on asphyxial nephritis, in which it might have been said that 
the great urinary secretion obtained after injecting salt solu- 
tions was due merely to the injection of so much water. 

4. Nephritis Due to Temporary Closure of the Renal Vessels 

As Max Herrmann first showed, direct interference with 
the blood supply to the kidney leads to very destructive changes 
in this organ in an incredibly short space of time — the output 
of urine falls or may be stopped entirely and albumin, casts, 
and blood are found in such as is secreted. If the kidneys are 
examined they are found swollen, maybe grayish, and to present 
varying degrees of hemorrhage into the kidney substance. 
The following experiment illustrates this: 

Experiment 95. — Belgian hare; weight 2335 grams. Fed hay 
oats, corn, and greens. Urine obtained with a catheter. The right 
renal artery and vein, and the left renal artery are clamped for one- 
half hour. 



Time. 


Urine in cc. 


Remarks. 


2.05 




0.008 gram morphin hydrochloric! given subcutaneously. 


2.15 


15.0 


Clear, brownish-yellow, faintly acid to litmus. No albumin. 






No casts. After catheterizing the animal is weighed. 


2.50 




Tied into holder. 


3.00 


0.5 


Right renal artery and vein and left renal artery are clamped. 


3.15 






3.30 




Clamps removed. 


3.45 






4.00 






4.15 


1.0 


Much albumin. Hyaline casts and red blood corpuscles. 


4.30 






4.45 


0.5 


Thick, turbid, acid to litmus. Full of albumin and casts. 


5.00 


0.8 


Same 


5.15 






5.30 


0.8 


Thick, turbid, acid to litmus. Full of albumin and casts. 


5.31 




Animal appears well, is killed. 



Autopsy. — Kidneys are swollen and deep red, but otherwise show 
nothing strikingly abnormal to the naked eye. 



1 Oscar Berghausen: Arch. Int. Med., 9, 137 (1912). 

2 Martin H. Fischer: Kolloid-Zeitschr., 5, 146 (1910) and page 438 of 
this volume. 



660 



(EDEMA AND NEPHRITIS 



The urinary output in this experiment is illustrated in curve 
c of Fig. 207. Let us now see how an animal similarly treated 

fares if it receives an in- 
travenous injection of a 
"physiological" m/8 (0.729 
per cent) sodium chlorid 
solution. Such an experi- 
ment serves to answer two 
important questions. First, 
is the giving of water to 
a case of " acute nephritis" 
dangerous because it "throws 
work on the kidney " and 
we need to " protect " this 
organ against doing any 
work; and second, does the 
administration of sodium 
chlorid aggravate such a 
nephritis because, as some 
say, it " further increases 
the work of the kidney " 
or because it " irritates " 
this organ? A no incon- 
siderable portion of the 
therapeutic world to-day in- 
sists on both restriction of 
water and of sodium chlorid 
in cases of acute nephritis. 
That both may be given 
and that the sodium chlo- 
rid, far from adding itself 
as a factor of evil to the 
water, really counteracts the 
only bad effects this has 
(through favoring the swell- 
ing of the kidney and wash- 
ing out salts) 

^ is shown by the 

Hours l 2 3 f results of Ex- 

Figure 207. periment 96. 





NEPHRITIS 



661 



Experiment 96. — Belgian hare; weight 2184 grams. Fed hay, 
oats, corn, and greens. Urine obtained with a catheter. The right 
renal artery and vein, and the left renal artery are clamped for one- 
half hour. Thereafter, 215 cc. of m/8 NaCl solution are injected at 
a uniform rate intravenously. 



Time. 


Urine in cc. 


Remarks. 


11.20 




0.016 gram morphin hydrochloric! given subcutaneously. 


11.40 


2.0 


Thick, yellow, turbid, acid to rosolic acid. No albumin. No 






casts. Catheterized and weighed. 


12.10 


2.0 


Same. Right renal artery and vein and left renal artery 






clamped. 


12.25 






12.40 


. 


Clamps removed. 


12.50 




Injection of m/8 NaCl into ear begun. Accident to needle 






interrupts injection for ten minutes. 


1.05 


2.0 


Full of albumin, epithelial, finely granular and hyaline casts. 


1.20 


4.7 


Acid to rosolic acid. Full of albumin, epithelial, finely gran- 






ular and hyaline casts. 


1.35 


12.0 


Clear as water. Albumin going down. It is noted that 






there is decidedly more albumin in this experiment than 






when m/2 NaCl is used, volume of urine duly considered. 


1.50 


12.5 


Decided drop in albumin. Still some casts. 


2.05 


15.0 


Clear as water. Albumin present in traces only. Occa- 






sional cast only. 


2.20 


18.5 


Same. Trace of albumin visible after standing. 


2.35 


19.0 f 




2.50 


20.0 


No albumin. No casts. 


3.05 


21.0 I 




3.06 




Killed. 



Autopsy. — Weight 2269 grams. 6 cc. fluid in peritoneum. Pleural 
and pericardial cavities dry. Nothing abnormal noted in any organ. 



The increased urinary output, in consequence of the injec- 
tion of the m/8 sodium chlorid solution, is clearly evident when 
curve b of Fig. 207, based on this experiment, is compared with 
curve c obtained in the previously described Experiment 95. 
We note, moreover, that with the concentration of sodium 
chlorid employed in Experiment 96 a not inconsiderable amount 
of the injected water is retained, in other words, the animal 
develops an oedema. Many clinicians who believe that sodium 
chlorid " leads to oedema" might be inclined to say that this 
experiment supports their contention. That it does not is shown 
by Experiment 97, in which an animal, again rendered ne- 
phritic by clamping the renal vessels, is again injected with the 
same amount of water at the same rate, but the concentration 
of the sodium chlorid is further increased (to m/2 NaCl, that 
is, 2.918 per cent). As the protocol and curve a of Fig. 207 
show, the urinary output under such circumstances is still 



662 



(EDEMA AXD NEPHRITIS 



further, really enormously, increased, and not only does no 
oedema develop, but the animal actually loses in weight. To 
the interpretation of these various findings, which it was entirely 
possible to predict, we shall come immediately. 

Experiment 97. — Black rabbit; weight 2778 grams. Fed hay, 
oats, corn, and greens. Urine obtained with a catheter. The right 
renal artery and vein, and the left renal artery were clamped for one- 
half hour. Thereafter, the animal received at a uniform rate an 
intravenous injection of 170 cc. m/2 (2.918%) sodium chlorid solu- 
tion. 



Urine in cc. 



Remarks. 




0.016 gram morphin hydrochloric! are given subcutaneously. 
Yellow, turbid, alkaline to litmus. No albumin. * No casts. 

After eatheterizing, the animal is weighed. 
Yellow, clear, alkaline. No albumin. No casts. Right 

renal artery and vein and left renal artery are clamped. 



Clamps removed. 

Intravenous injection of m/2 NaCl begun. 
Filled with casts and red blood corpuscles. 

albumin. 
Last portions clear as water. 



Fairly sets with 



Clear as water. Acid to phenolphthalein, alkaline to rosolic 
acid. Faintest trace of albumin only. No casts. Occa- 
sional red blood corpuscles. 

Animal killed. Approximately 10 cc. urine lost in interval 
between stopping injection and making autopsy. 



Autopsy. — Weight 2554 grams! 19 cc. fluid found in peritoneal 
cavity. Pleural and pericardial cavities are dry. Kidneys are slightly 
grayish. 

Experiment 98 shows for what a long period the blood supply 
to the kidney may be cut off and yet the dangers ordinarily 
incident to such a procedure (partial to complete suppression 
of urine) be reduced by giving a concentrated salt solution. 
The experiment was really undertaken to indicate how the 
so-feared consequences of temporary occlusion of the blood vessels 
in operations on the kidney may be largely avoided or over- 
come — a discussion to which we shall return later. 



Experiment 98. — White and blue rabbit; weight 2344 grams. 
Fed hay, oats, com, and greens. Urine obtained with a catheter. 
The right renal artery and vein and the left renal artery and vein are 



NEPHRITIS 



663 



clamped for 1| hours. After an interval, 90 cc. m/2 NaCl are injected 
at a uniform rate intravenously. 



Time. 



Urine in cc. 



Remarks. 



9.20 
9.50 
10.05 

10.20 
10.35 
10.50 
11.05 
11.20 
11.35 
11.50 
12.05 
12.20 
12.35 
12.50 

1.05 

1.20 

1 35 

1.55 

2.10 

2.25 

2.40 

2.55 

3.10 

3.25 

3.40 

3.55 

3 . 55 to 

5.25 

5.40 

5.41 



1.3 



0.3 
0.4 
0.4 
0.8 

2.6 
2.8 
1.5 

11.3 

1.5 



0.016 gram morphin hydrochlorid are given subcutaneously. 
Tied down. Catheterized. 

Deep brownish-yellow. No albumin. No casts. Renal 
blood vessels are clamped. 



Clamps removed. 



Injection of m/2 NaCl into ear begun. 



Filled with albumin and hyaline casts (exclusively). 

Injection stopped. 
Urine clearer. Filled with hyaline and granular casts. 
Casts fewer. 
No casts. 

No casts. Red blood corpuscles found (traumatic). 
No 

Killed 



Autopsy. — Weight 2300 grams. 10 cc. fluid in peritoneal cavity. 
1.2 cc. in right pleural cavity. Left unusually moist. Kidneys soft 
and somewhat gray. 

The secretion of urine in this experiment is represented graph- 
ically in Fig. 208. The first arrow indicates the point in the 
experiment when the clamps were removed. Up to the point of 
the second arrow no urine was obtained. At this time the sodium 
chlorid injection was started. The secretion of urine began 
less than half an hour afterwards. 

5. Interpretation of Experimental Findings 

It behooves us now to study the experiments just described 
in order to discover the 'principles that underlie the results obtained, 
for only by knowing these can we hope to put them to any intel- 
ligent therapeutic use. In the light of the facts developed in 



664 



(EDEMA AND NEPHRITIS 



the earlier pages of this volume it follows that the living organ- 
ism represents in the resting state a series of colloids saturated 
with water. The slight (normal) secretion of urine observed 
in an animal which is quietly tied into an 
animal holder represents a certain amount of 
" free " water still available for secretion. 
When we tie such a normal rabbit into an 
animal holder sufficiently snugly to interfere 
with its easy respiration the urinary output 
falls, as shown in Fig. 202. This is because 
by such means the accumulation of carbonic 
and other acids in its body is favored, which 
increases the capacity of the body colloids 
for holding water. None is therefore left 
over to be secreted as urine. The animal is, 
in other words, at once put into a condition 
similar to that attained after several hours 
if it is simply kept off food and water. 
Parenthetically we may add that a similar 
asphyxial state, induced here by tying the 
animal into a holder, is obtained by chemical 
means when we give a dose of morphin, 
cocain, atropin, or arsenic, an anesthetic like 
chloroform or ether, an excessive dose of alco- 
hol, or a nitrite. 

The same increased hydration capacity of 
the kidney colloids and the body colloids 
generally is produced if we inject acid in- 
travenously. The acid acts upon them and 
they therefore absorb and hold on to any 
water that may be given to them in these 
experiments along with the acid. Again none 
remains over to be secreted by the kidney. 
The animal retains the water and increases 
° "* **g° in weight, in other words, it develops an 

" cedema." 

To the relief of .all these conditions comes the administration 
of salt (along with the water). The salts — including sodium 
chlorid — reduce the amount of water that can be held by the 
body colloids generally, and so this freed water now becomes 



NEPHRITIS 



665 



available for urine. The kidney itself shares in this process and 
by shrinking admits a better circulation to be once more estab- 
lished through it. The body now loses water, and so the animal 
loses weight, in other words, the cedema disappears. The kidney 
proteins become less soluble and so the albuminuria goes. 

Following a sudden apparent increase in number, the casts 
go. The apparent increase is due to the shrinkage, under the 
influence of the increased salt concentration, of the casts as they 
lie in the kidney tubules, followed by their easier and sudden 
washing out by the increased urinary flow. They tend, more- 
over, to change from the hyaline type to the granular, the latter 
representing reconversions from the hyaline under the influence 
of the salt. 

6. Inhibitive Effects of Alkaline Salts on the Albuminuria of 

Hard Work 

We shall conclude this section by giving a concrete illus- 
tration of the fact that, by increasing the alkali-salt content 
of the body, the opportunities for the development of the signs 
of a nephritis are greatly reduced. For such a test the albumi- 
nuria that develops in athletes after hard work was used, and 
with the following results: 

In Experiment 63 on page 493 were detailed the quantitative 
findings regarding the excretion of albumin during an ordinary 
match basket-ball game, as determined by collecting the urine 
over the period of an hour and a half, in which time the game 
was played. In the following two experiments the urine was 
similarly collected, every precaution being taken to have the 
conditions for collection, regarding time, etc., as nearly the same 
as in the control. The athletes were under no restrictions regard- 
ing diet, the only difference being that in the two experiments 
now to be detailed, they took in addition to their ordinary food 
the juice of six sweet oranges in the first, and twelve in the second. 
The six oranges were consumed in the course of three hours pre- 
ceding the game; the twelve in the twelve hours preceding the 
game. Oranges were chosen not alone because they are palatable 
and so offer no difficulty in having the men take them, but 
because the salts contained in them have not only a decided 
capacity for combining with stronger acids but because the 



666 



(EDEMA AND NEPHRITIS 



citrates, malates, etc., are the very salts which act most power- 
fully in reducing the solubility of proteins in acids (the swelling 
of organs, etc.). The game played in Experiment 99 was decidedly 
harder than that detailed for control purposes in Experiment 
63, that of Experiment 100 fully as hard. The first five players 
were the same in all these three games, though the order in 
which they are numbered is not the same. 

Experiment 99. — Juice of six oranges fed the plaj^ers. Urine 
collected for period of If hours, during which time the play occurred. 
Phosphotungstic-hydrochloric acid-alcohol reagent used in the Esbach 
albuminometer. 



Before the Game 



Player. 


Urine in cc. 


Nitric acid test. 


Heat test. 


1 


232 


Negative 


Negative 


2 


72 


Negative 


Negative 


3 


30 


Negative 


Negative 


4 


85 


Negative 


Negative 


5 


280 


Negative 


Negative 



After the Game 



Player. 


Urine in cc. 


HNOs test. 


Heat test. 


Esbach 
reading. 


Albumin 
excreted, 
in grams. 


1 


62 


Positive 


Positive 


1.25 


.078 


2 


17 


Positive 


Positive 


1.5 


.025 


3 


152 


Positive 


Positive 


0.75 


.114 


4 


42 


Positive 


Positive 


0.75 


.132 


5 


228 


Positive 


Positive 


less than 0.2 ' 


.046 












Av. .079 



Experiment 100. — Juice of twelve oranges fed each of the players. 
Urine collected for period of If hours, during which time the play 
occurred. Phosphotungstic-hydrochloric acid-alcohol reagent used in 
Esbach albuminometer. 



Before the Game 



Player. 


Urine in cc. 


Nitric acid test. 


Heat test. 


1 


73 


Negative 


Negative 


2 


170 


Negative 


Negative 


3 


187 


Negative 


Negative 


4 


6 


Negative 


Negative 


5 


23 


Negative 


Negative 


6 


62 


Negative 


Negative 



NEPHRITIS 667 



After the Game 



Player. 


Urine in cc. 


HNOa test. 


Heat test. 


"P 1 , CR AflT 

reading. 


Total albu- 
min excreted, 
in grams. 


1 


97 


Positive 


Positive 


0.75 


.073 


2 


56 


Positive 


Positive 


1.25 


.070 


3 


11 


Positive 


Positive 


1.6 


.018 


4 


44 


Positive 


Positive 


1.3 


.057 












Av. .054 


5 


44 


Positive 


Positive 


0.6 


.028 


6 


45 


Positive 


Positive 


0.25 


.011 



Player number 5 played first half only; number 6, second half only. 



Even when we count out the player in the control game • 
who started with an albuminuria, and those in the succeeding 
games who did not play through, we still find that the albumin 
excretion, both so far as average concentration and average absolute 
amount is concerned, is decidedly lower after feeding citrus fruit 
than without such feeding. 

XI 

ON THE TREATMENT OF NEPHRITIS 

1. Introductory Remarks 

For the treatment of nephritis everything has been suggested 
from prayer to hot irons down the back. A discussion of the 
subject can therefore scarcely bring the mention of anything 
new that might be tried. ' It can hope to be of interest or impor- 
tance only as, on the basis of the views entertained by an author 
regarding the nature and the cause of nephritis, he will assign to 
certain practices grades of importance different from those 
assigned to these same practices by another — a difference of 
opinion that may perhaps be carried to the point where the 
one will find virtue in procedures that another regards only 
as evil, and vice versa. Were we to formulate a general rule 
for the prophylaxis and for the treatment of nephritis we should 
evidently have to say that this lies in an avoidance and removal 
as far as possible, of every condition that favors the abnormal pro- 



668 



(EDEMA AND NEPHRITIS 



duction or accumulation of acids in the kidney, or of such other 
substances which in their effects on the colloids behave like acid. 

It therefore becomes necessary in approaching any case of 
nephritis first to get as clear a conception as possible of all 
the factors conspiring toward the production or maintenance of 
the abnormal content of acid and like sue stances in the kidney. 
Rarely shall we find but one factor active. To the toxic cause 
of a scarlatinal nephritis may be added that of an inadequate 
lung ventilation if the patient develops a bronchopneumonia. 
To the toxic nephritis of a pneumococcus infection already 
aggravated by a decrease in available lung for respiratory pur- 
poses, may be added an additional item if the patient develops 
a convulsion and so (through muscular work) produces suddenly 
an enormous additional amount of acid. The eclamptic patient 
who has just managed to drag through the last weeks of pregnancy 
faces death when the muscular efforts of labor or of a convulsion 
add more acid to that resulting from the intoxication of pregnancy. 
The patient with subacute or chronic nephritis, who, with per- 
sistent cedema, some casts, albumin and a deficient output of 
urine, is permitted or insists on working about the ward, may 
be breaking the camel's back with this added straw of acid 
production by even such light muscular work. 

After we have, through restriction of muscular and mental 
effort, through rest in bed, through an adequate supply of fresh 
air, etc., removed as many of these conditions as possible, we 
turn our attention to combating those which we cannot remove. 
The rule to be followed then may be summarized in these words : 
Give alkali, salts, and water. To this may be added a fourth 
bidding: Give dextrose (glucose) or, if the conditions for its proper 
utilization are present in the body, some other sugar or starch. 
The reasons for all this are, of course, apparent. The alkali 
is given to neutralize the acid present in abnormal amount in 
the kidney (and the other cedematous organs of the body). The 
salts are indicated (and sodium chlorid is no exception) because 
the various changes induced in such colloids as constitute the 
kidney by the action of acid upon them, are counteracted by 
adding to such acid any salt, even a neutral salt. We need to 
give water in order to have this present in the body over and above 
the amount necessary to saturate all the body colloids; other- 
wise we shall have no " free " water left over out of which to make 



NEPHRITIS 



669 



urine. Dextrose or other carbohydrates are necessary, not alone 
from a chemical point of view, in that an abnormal production 
and accumulation of acid in the body is frequently the conse- 
quence of carbohydrate starvation, but because the sugars are 
peculiarly powerful in reducing certain types of increased hydra- 
tion in proteins not produced by acids. 

The exact methods to be adopted, the aggressiveness and 
persistence with which this simple rule is followed, and the results 
obtained by so doing must evidently depend upon the condition 
or combination of pathological conditions that our patient may 
have developed, and which we hold responsible for the abnormal 
production or accumulation of acid and like substances in his 
kidneys. Evidently an anesthesia nephritis with suppression 
of urine will call for a more aggressive therapy than a nephri- 
tis secondary to a slowly progressing arteriosclerosis. On the 
other hand, if we succeed in getting our first nephritic over his 
immediate kidney symptoms we may make a hopeful prognosis, 
for when he has exhaled his anesthetic he has rid himself of the 
condition that was responsible for the abnormal acid content in 
his kidneys. But in our second nephritic so hopeful a prognosis 
cannot be made, for while we may also benefit him, he continues 
to carry the original condition that brought him to us — his 
arteriosclerosis — even after we have treated him. 

2. Diet in Nephritis 

We have long paid attention to the diet in nephritis. Clearly, 
the direct consumption of acid as such by the nephritic is con- 
traindicated. The mineral acids which would be worst in 
this regard do not enter into our foods to any appreciable extent, 
though in the forms of fruits, sour wines, etc., not inconsiderable 
amounts of organic acids are swallowed. With the exception 
of benzoic, oxalic and tartaric acids, most of these undergo 
oxidation in the body rather easily, being converted into carbonic 
acid, which is readily excreted. The organic acids are therefore 
less poisonous than might at first appear. But from this is 
not to be concluded that they are of no importance at all. Not 
only are certain " weak " organic acids (notably, tartaric, acetic', 
and lactic) quite as active physiologically as the " stronger " 
acids, but consumed in excessive amounts they are not without 



670 



(EDEMA AND NEPHRITIS 



effect even in "normal" individual.?, as witness the oedemas 
observed in children that are fed buttermilk. 1 the urticarias 
following the consumption of excessive amounts of grapes. 2 
etc. In nephritics these organic acids assume a yet more 
important role, for these individuals have, for various reasons, 
a decidedly decreased capacity for properly oxidizing them. 

Still it is not to be concluded that every article of diet which 
yields some of these organic acids is therefore at once to be 
excluded. Such measures all too often lead to the absurd food 
restrictions with which patients are constantly tortured. Their 
importance need only be recognized to the end that an adequate 
amount of alkali, for example an alkaline water, be fed along 
with the food containing the organic acids. 

In the metabolism of proteins not inconsiderable amounts 
of acid are produced. 3 Herein is to be sought at least part 
of the explanation of why a restriction of the proteins in nephritis 
is of use. If improperly used in the body, the proteins may. 
moreover, yield other than the normal amins. in other words, 
toxins which like acids are capable of increasing the hydration 
capacity of the body proteins and otherwise influencing their 
state. In the absence of sufficient carbohydrate, the fats may 
also yield abnormal or abnormally great amounts of such acids 
as diacetic. beta-oxybutyric. etc. But before one proceeds to a 
too drastic revision of the dietary, a process in which we are 
particularly liable to eliminate the proteins too vigorously, the 
absolute amounts of acid formed by the various constituents 
of the food should be considered. When this is done it will be 
found that the evil consequences expressed in terms of a direct 
acid yield from the proteins of our food, for example, are small 
compared with those that may be calculated from a bottle of 
dry wine. Consideration of the acid content of alcoholic beverages 

1 Ernst Scheoss: Deut. med. Wochenschr., No. 22 (1910). Schloss 
does not. however, consider this an oedema due to feeding acid, but as 
"idiopathic*" He found it to disappear on administering calcium salts. 

2 Personal observation. The urticaria disappears as soon as calcium 
salts are given, or fails to aooear if such are consumed with the grapes. 

3 G. vox Bvnge: Zeitschr. f. Biol.. 10. Ill 1574 : X. Lrxrx: Zeitschr. 
f. physioh Chem.. o, 31 1551 : Emil Abderhalben: Biochem. Zentralbl 
2, 257 1904 . See also the important studies on the balance of acid-form- 
ing and base-forming elements in food by H. C. Sheemax and A. 0. Gettler: 
Proc. Soc, Exp. Biol, and Med.. S. 119 1911 : X. R. Blatherwtck: Arch. 
Int. Med.. 14, 409 1914; . 



NEPHRITIS 



671 



helps us, moreover, to understand why some of these exercise a 
worse effect in nephritis than others. We have long recognized 
that the alcohol content is not alone responsible for the effects 
of alcoholic beverages in kidney disease, for while it is true that 
in large doses alcohol allies itself with the general anesthetics, 
small doses do not interfere with the oxidative reactions in the 
living cells, but rather favor these (and so kidney function). 
But whatever is fed, it is clear that all the acid effects of the food 
need not appear if we will take the precaution of seeing that the 
diet contains sufficient alkali to neutralize the acid. 

Just as certain features of a dietary thus favor the develop- 
ment of a nephritis, so also do others counteract it. Most 
notable here are the long-observed beneficent effects that follow 
the use of alkalies and the substitution of a more strictly fruit 
and vegetable diet for our ordinary mixed diet. The bases 
present in fruits and vegetables are from the start combined with 
weak organic acids which in the body are largely oxidized to car- 
bonic acid. How successfully a diet rich in fruits and vegetables 
counteracts even the normal tendency of the body to run toward 
the acid side is a matter of common knowledge to any physician 
who has watched the urine of his patients turn from its normal 
acidity to an alkalinity, when ordered from an ordinary mixed 
diet upon one richer in the vegetables and fruits. 

But this neutralization capacity of the fruit and vegetable 
diet for acids is not the only factor which accounts for its 
beneficent effect. We learned earlier that the solubility of 
protein in any acid is markedly reduced by salts. Not only 
are the vegetables rich in salts, but they are rich in the very 
ones which act most powerfully in reducing the solubility of the 
protein. So we may find in this fact, along with what has already 
been said regarding the capacity of the vegetable diet to neutralize 
acids, a satisfactory scientific foundation for the reduction of 
the albuminuria in nephritis, when a diet rich in vegetables 
follows one in which these were not so abundant. Such salts 
also serve to reduce the size (swelling) of the kidney, and as 
we have seen, they practically prevent those precipitation effects 
in the kidney cells (granule formation) that are characteristic 
of the early changes of nephritis from a morphological point 
of view. Speaking generally, a diet high in fruits and vegetables 
also means that the individual is consuming more water. The 



672 



(EDEMA AND NEPHRITIS 



effect of this will be discussed later, but even now it may be 
pointed out that such will aid our nephritic, because it brings 
to his kidney the " free " water from which alone he can make 
urine. 

Practically expressed, I let the nephritic eat pretty much 
as he pleases. In the ambulatory subacute or chronic cases 
associated with blood vessel disease or secondary to infections 
of the kidney I permit a moderate meat ration on condition 
that the patient will eat his vegetables first. This trick in- 
creases his alkali intake at the expense of the acid side of his 
dietary. The soups are not forbidden, because the salts and 
water thus consumed offset largely any bad effects which the 
accompanying meat extractives are imagined to have. If the 
proteins are thought to be giving rise to " autointoxication " 
products in the alimentary tract, I use small doses of calomel 
or occasional large enemas of salt solution, sodium bicarbo- 
nate or soap. Enemas of sodium bicarbonate (two level table- 
spoonsful in two quarts of warm — not hot — water) are especially 
to be recommended. Calomel in small doses does not injure 
the kidneys, but exercises only the dehydrating effect upon 
all the body colloids, which increases secretion from the ali- 
mentary tract and the kidneys. Since even large amounts 
of fruits and vegetables may not prove sufficient to keep the 
patient well supplied with alkali, I urge the daily use of suffi- 
cient natural or artificial alkaline waters, either carbonated or still, 
to accomplish this purpose. A patient is getting enough 
alkali when his urine is kept persistently neutral to litmus. He 
should be given neither more nor less than this amount. I teach 
the ambulatory nephritic to test his own urine and to increase or 
decrease his alkali intake as necessary. 1 

The bedridden cases are treated from a dietary point of 
view in the same fashion. More harm is done these patients by 
underfeeding them than by overfeeding. The caloric needs of 
the individual must be covered daily. A "starvation acidosis" 
is as bad as any other kind. Orange juice, grape fruit juice, 

1 To escape the effect of alkali upon the stomach and obtain it in the 
small intestine E. G. Ballenger and O. F. Elder (Jour. Am. Med. Assoc., 
62, 197 (1914) ) suggest its administration in admixture with mutton suet 
and paraffin. They further make use of the clever expedient of adding a 
little phenolsulphonephthalein. The patient then knows that he is con- 
suming enough alkali as soon as he voids a constantly pink urine, 



NEPHRITIS 



673 



lemonade, cereals, milk and cream, vegetables, fruits, and 
various meats and fish should in the order named be urged upon 
the nephritic. Such foods as will carry it should have sugar 
added to them, for the first items in which our diets are likely 
to be short are the carbohydrates. . 

These patients also are given an alkaline water of some sort. 
The natural or artificial alkaline spring waters are perhaps most 
easily borne. If the patient will tolerate it, 0.5 to 1.0 gram 
of sodium carbonate or sodium bicarbonate may be added to 
each glass of such alkaline water, or to plain water. Some patients 
who cannot tolerate the carbonates will take sodium citrate, 
sodium tartrate, 1 sodium acetate or other salts of a strong base 
with a weak acid in half-gram or larger doses every hour, either 
when dissolved in water or in capsules followed by water. Cal- 
cium hydroxid can easily be given by mixing lime-water with 
milk. As the salts of the bivalent metals are particularly active 
in decreasing the hydration-capacity of the body-colloids, the 
administration of magnesium oxid or milk of magnesia up to the 
point where two or three easy movements of the bowels are 
obtained daily, gives good results. The soluble salts of calcium 
and strontium, as the iodids, acetates, lactates or citrates are 
to be highly recommended. They are, unfortunately, absorbed 
rather slowly, but once in the body they keep the hydration 
capacity of the body colloids low. The same is true for the salts 
of iron which the older doctors used so effectively. 

For reasons discussed before, I do not think that table 
salt should be restricted in a threatened or developed nephritic, 
but on the contrary should be urged upon the patient. Food 
serves as a natural carrier for this. In the form of salt meats 

1 Tartaric acid is little, if at all, oxidized in the body. Its appearance 
in the body therefore draws upon the alkali contained therein and empha- 
sizes the necessity of seeing to it that foods rich in this acid (as grapes) are 
accompanied by sufficient fixed alkali to do away with the acid effect. 
Underbill, Wells, and others have reported deleterious effects upon the 
kidneys from feeding tartrates, but W. E. Post (Jour. Am. Med. Assoc., 
62, 592 (1914)) noticed none when up to 24 grams were given to nephritics; 
in fact he noticed nothing but good results to follow the use of sodium and 
potassium tartrates — as the older doctors have so long known. William 
Salant (Jour. Am. Med. Assoc., 63, 1076 (1914)) noticed poisonous effects 
in rabbits on an oat diet but not on a diet of carrots. But an oat diet as 
Weiske has shown is an "acid" diet and one insufficient in calcium. As 
Salant also observed, calcium administration does away with the poisonous 
tartrate effect. 



674 



(EDEMA AND NEPHRITIS 



and salt fish we can easily get considerable quantities of sodium 
chlorid into our patient, and by placing a salt shaker at hand, 
he can liberally increase his intake by dusting it on his vegetables, 
his fats, and such proteins as we allow him. 

Through the diet alone we can, therefore, do a great deal to 
keep the intake of alkali and salts high. 

3. Water Consumption in Nephritis 

The question of water consumption resolves itself into two 
parts — into the use of water in cases where a nephritis is likely 
to arise, and into its use in an established case. The reasons 
are obvious why water needs to be given in the first instance and 
why we wish to give it at a uniform rate in the largest possible 
amounts that will not injure the patient. Not only must the 
patient get water in order to have the wherewithal to make urine, 
but, whatever the conditions lying behind the nephritis, the patho- 
logical state amounts in the end to an intoxication. This is strik- 
ingly true, of course, in the infectious diseases or in an eclampsia 
case. Here the whole organism is suffering from the effects of a 
poison. The effect of that poison depends not alone upon the 
length of time that it acts upon the organism as a whole or any 
individual part of it, but upon its concentration at any one time. If 
now our interest centers upon a toxic effect that such a poison may 
have upon the kidney, and we are anxious to protect this organ, 
it is clear that the concentration of the poison must be kept 
as low as possible in it. To do this only two possibilities are 
open, and when we cannot control the factor of poison produc- 
tion, we can hope to cut down the effect of the poison only by 
keeping what is produced as dilute as possible. This calls for 
the giving of water. In this connection the practical point should 
be remembered that in ordinary practice an ever so patient admin- 
istration of water through the day is likely to be neglected in the 
night. As toxin production does not cease with nightfall, it is 
clear that water administration also should not, otherwise we are 
likely to lose in a few hours at night what we cannot subsequently 
regain in days, if at all. The administration of water cannot 
therefore be left to the haphazard desire of the patient. It must 
be insisted upon in a regular manner. A good rule is to give half 
a glass every hour day and night. 



NEPHRITIS 675 

At this point we are likely to be met by the argument that 
while such a water therapy is accepted as advisable in the 
toxic nephritides, those associated with heart lesions, etc., are 
not to be similarly treated. Let us first point out that these 
too are toxic nephritides — the patient with a broken heart com- 
pensation, or a compressed lung due to a carcinomatous pleurisy, 
and albumin in his urine shows this (according to our views), 
because the acid content in his kidneys is abnormally high. The 
more the concentration of this can be reduced the less will be 
its effect on the kidneys. Thus far, therefore, he needs water 
quite as much as the nephritic who is such in consequence of an 
infectious disease. 

But it has been argued that the giving of water increases the 
work of the heart in these cases, and so is bad. I have been unable 
to discover where this notion first arose. It is apparently some- 
body's clinical guess, for there exist no physiological proofs for 
such a belief. If it is reasoned that the work of the heart is 
increased because more water secretion calls for more filtration 
pressure and this in turn requires more blood pressure, and there- 
fore more work from the heart, then the reasoning is technically 
correct. But if it is remembered that ten to fifteen millimeters 
of mercury pressure suffice for all this, then the maintenance 
of this fraction of the physiological average of one hundred and 
twenty-five millimeters required for all circulation purposes can 
hardly be looked upon as much of a burden to the heart. As a 
matter of fact it is the viscosity of the blood which determines in 
good measure the amount of work the heart must do in pumping 
it. The addition of water does not increase this, but decreases it. 

If the whole matter is reduced to the simple statement that the 
giving of plain water may aggravate some of the signs of a nephritis 
(like the generalized oedema) then no quarrel is to be had with it. 
What is observed is not, however, the consequence of a little 
water administration upon cardiac activity. 

The only objections that may be raised against a too vigorous 
administration of water are two. The first is associated with the 
fact that when the hydration capacity of any tissue has been increased 
(as that of the kidney in nephritis) the giving of water permits it to 
swell; the second with the fact that pure water in washing through the 
kidney washes out not only poisonous substances of which we would 
be rid, but good salts of various kinds in addition. Thus, it might be 



■ 



(EDEMA AND NEPHRITIS 



reasoned that to give water in the aeuter forms of nephritis would 
be to aid this swelling. Such swelling of the cells, so far as the 
cells themselves are concerned, can hardly he considered serious, 
any more than a moderate oedema of any tissue is in itself particu- 
larly destructive to the tissue, But in the case of the kidney a 
complicating circumstance arises which does make such a swell- 
ing dangerous. This resides in the fact that the capsule of the 
kidney is not as expansile as the rest of the kidney substance. As 
the kidney substance swells, this tends, therefore, to press upon 
- the blood vessels and retard the circulation of the blood through 
the kidney. This condition actually comes to pass. Thus, a 
kidney already nephritic, say from the toxin of an infectious disease 
or an anesthetic, aggravates its state by hampering its own blood 
supply. 

The washing out of salts from the kidney acts in the same 
direction, for, as already noted, these tend to counteract the 
swelling. Our problem might, therefore, seem to become that 
of balancing the good effects of water against certain bad ones. 
Actually it is much simpler. We give the kidney the benefit of the 
virtues of water, while we prated it at the same time from the dangers 
associated therewith by giving along with the water properly chosen 
setts in sufficient amount. 

4. The Role of Salts in Nephritis 

In our every-day diet we never seriously consider whether 
we drink distilled water, tap water, or a table water. Ani 
from this point of view we might be inclined to ignore the exact 
composition of the liquids consumed by a nephritic. But let 
us look at the problem a little more critically. The normal 
individual does not really with impunity ignore the matter. It 
only seems so. In his food he consumes large quantities of 
various salts, so what he really obtains in any longer interval 
of time is a salt solution- The proper regulation of this — that 
is to say. the continuous consumption of a proper salt solution 
which in its turn maintains a proper salt concentration in and 
about the various cells in the body — is accomplished through 
the " taste " of the individual. If his salt consumption has been 
too high, he craves fresh water, and so washes out the excess. 
If on the other hand, he has lost too great an amount of salt 



NEPHRITIS 677 

he consumes more and makes up the deficit. The truth of these 
statements is attested by the most varied scientific and social 
facts. The animal treated with a strong salt solution makes 
desperate efforts to get at water, and the salt-starved animal 
licks the sides of its cage and laps up its urine. The American 
retailer of beer feeds his customers salt meat and fish gratis. 
This gives them a thirst which they satisfy with beer, and over- 
drinking, they turn about and demand more salt food. 

If these facts are borne in mind, it becomes easy not only 
to devise a therapy which from present evidence promises most 
in the relief of nephritis and allied conditions but to recognize 
the merits of long recognized therapeutic procedures. 

The milk diet has, not without reason, been popular. By 
giving milk we give a patient a useful balanced ration of fat, 
carbohydrate, and protein. But we do more than this — we give 
water and salts. The water helps to wash out poisons and 
the salts contained in the milk have a concentration which just 
suffices to do away with the effects of giving an equal amount 
of water pure. 

Similar reasoning explains the beneficent effects of giving 
" physiological " salt solution in large amounts by rectum, 
intravenously or subcutaneously, in various acute infections 
It is again the combined effects of much water to wash out poi- 
sons, and enough salt to counteract that accidentally lost 1 by 
the same process that washes out the poison. When in spite 
of such procedures the signs of a nephritis develop we need to 
press more salt (alkali and sugar). 

In the nephritic, because of the accumulation of substances 
in parts or all of his kidneys or other organs, which increase 
their hydration capacity, these are abnormally swelled. To 
reduce their swelling a more than " physiological " concen- 
tration is demanded. To accomplish this the patient must 
consume a proportionately larger amount of salt. This is a 
matter which for various reasons we cannot leave to his taste 
alone. We need in consequence to give him specific instruc- 

1 We have become all too inclined to consider everything that comes out 
in the urine as something that the intelligence of the kidney has found 
harmful to the body. It is scarcely as wise as this. It is rather hard to see, 
for example, why, in a. salt-starved animal that is being given water, the 
animal continues to eliminate some salt in the urine up to the moment of 
death, when it is this very elimination that is killing the animal. 



678 



(EDEMA AND NEPHRITIS 



tions as to how to increase his salt intake. As previously 
noted, sodium chlorid forms no exception to this rule. There 
are, however, many other and more powerfully effective salts, 
and herein lies the scientific reason for the so-long established 
custom of giving these patients the acetates, tartrates, cit- 
rates, etc., of sodium and potassium, as well as magnesium 
sulphate, magnesium citrate, Basham's mixture, etc. These 
are all salts which in low concentration produce great dehy- 
drating effects in all the tissues of the body. -Such salts there- 
fore permit us by keeping the hydration capacity of the body 
colloids low, to get the beneficent washing-out effects of water 
without its deleterious consequences. 

5. More Aggressive Methods of Alkali and Salt Administration 

Let us now imagine that in spite of these procedures the 
nephritic 's symptoms do not improve. Many patients cannot 
long keep up a high consumption of alkali and salt by mouth. 
They may begin to vomit; or a " uremia " with vomiting may 
develop so that we may fail in our therapy. Or let us imagine 
that the symptoms are rather severe from the start, so that alkali 
and salt by mouth seem inadequate. What are we then to do? 

We continue to get as much use out of the gastric route as 
we can, but we use the rectum also in order to get an absorption 
of alkali, salt and water. 

Here again a more than " physiological " concentration of 
salt is demanded. A " hypertonic " solution is necessary. To 
reduce the oedema in the kidney or in the brain, in the optic 
nerve or in the tissues generally, we need to try to increase, at 
least temporarily, the absolute concentration of salt in the whole 
body. We therefore use a hypertonic salt solution to which has 
been added an alkali. Obviously, when using such a hypertonic 
solution by rectum we do not allow pure water or any solution of 
low concentration to be taken by mouth. The patient may wet 
his mouth to relieve his sense of thirst, but no more, otherwise 
we only reduce the concentration and so the therapeutic value 
of the solution we are administering by rectum. 

After much experience I have found the following procedure 
most simple and effective and now use it more often than any 
other. If the attending physician will but consider the patient 



NEPHRITIS 



679 



as a mass of swollen protein and keep in mind that the signs and 
symptoms which he is asked to treat are but the expression of this 
swelling either in the mass as a whole or in some particularly 
affected part thereof, like a kidney — and that the methods for 
securing dehydration of the affected parts (and therewith of the 
signs and symptoms referable to that part) are limited in the 
light of our present knowledge to an attainment of water evapora- 
tion from the affected part and its effective dehydration through 
an increase in the content of alkali and salt in the affected part — he 
will recognize quickly the reasons for the following categorical 
rules. 

1. Stop all water by mouth for as long a period as may be neces- 
sary. Six to eight hours may suffice, but if the symptoms still 
persist this period may be doubled or trebled. 

2. Give an {hypertonic) enema of baking soda water (two rounded 
tablespoansful of baking soda to two quarts of warm, not hot, 1 
water). The injected solution may be rejected like any ordinary 
cleansing enema. A goodly amount of the strongly alkaline salt 
is nevertheless absorbed. Repeat the enema in two, three or four 
hours, depending upon the urgency of the case, and then every 
four, six or eight hours and finally night and morning only. The 
number necessary is determined by the state of the patient and 
by the reaction of his urine. Enough alkali must be given so 
that every specimen of urine is alkaline to litmus or methyl red 
paper. 2 

3. Give a teaspoonful of saturated solution cf magnesium sul- 
phate by mouth every hour for six to eight doses. This is the strongest 
dehydrating salt that is readily absorbable. While such a dose 
may produce catharsis this is not to be taken as the real index to 
the effectiveness of its action. It is the salt that is absorbed 
into the tissues that produces the effect desired and this may be 
obtained with no catharsis whatsoever. 

How long must such therapy be persisted in? The alkali 
administration may be used indefinitely, analysis of the urine 
alone being an index to its quantitative efficiency. The index 
to an effective salting of the patient's tissues is found in a dis- 
appearance of his symptoms (better urinary secretion, awakening 

1 Sodium bicarbonate is decomposed to sodium carbonate at 70° C. 
(158° F.). The latter does no harm but is more irritating. 

2 See page 772. 



680 



(EDEMA AND NEPHRITIS 



from coma, decrease in intraocular tension) or, if conscious, in 
the development of thirst. The patient must obviously be kept 
in such a state of thirst — in other words, be permitted nothing but 
hypertonic salt and alkali mixtures (and when fed, as dry a diet 
as possible) — until sufficient time has elapsed to permit of the 
removal of those first pathological circumstances which led to the 
nephritis, " uremia" or glaucoma for which he summoned aid. 

It must be clearly understood that there is nothing specific 
about the scheme of treatment just outlined. It only repre- 
sents one method of producing an adequate alkalinization and 
salt dehydration. 

A formula 1 which I employ more commonly when intra- 
venous measures are necessary but which may be used by rectum 
and with good results is the following: 

Sodium carbonate (Na 2 C0 3 • 10H 2 O) 10 grams 

Sodium chlorid 14 grams 

Distilled water, enough to make 1000 cc. 

Simple as is this formula, care must be taken in its prepara- 
tion if good effects are expected. While we need not for rectal 
use insist upon the same grade of care that is necessary when such 
a solution is to be injected intravenously, it is well to consider 
everything even here. 

Sodium carbonate is -used, not bicarbonate. The carbonate 
is physiologically more effective than the bicarbonate, for one of 
the acids which is produced in the body is carbonic acid, and 
sodium bicarbonate is already saturated with this. In con- 
sequence, it cannot act as a carrier for it. 

The chemically pure, crystallized sodium carbonate 
(Na 2 CO 3 10H 2 O) or the monohydrated form (Na 2 C0 3 -H 2 0) 
is to be insisted upon. Two other forms of sodium carbonate 
are found in the market, the dry (Na 2 COs), and the so-called 
dry or " dried." The "dried " salt found on the ordinary drug 
shelf contains approximately two molecules of water of crys- 
stallization (Na 2 CC>3 ■ 2H 2 0) . We are inclined to advise against 
all except the large crystallized form or the monohydrated 
form; but whatever salt is used its content of water of crystalliza- 
tion must be remembered, otherwise a solution of a different strength 
from that which has been found most useful will be obtained. 

1 This is the solution frequently called by my name. 



NEPHRITIS 



681 



The proportionate amounts of these four salts that may be 
used are to each other as their molecular weights, or, in definite 
terms: 

10.00 grams Na 2 C0 3 - 10H 2 O (molecular weight 286) crystallized "sal-soda " = 
4 . 95 grams Na 2 C0 3 • 2H 2 (molecular weight 142) " dried " 
4.33 grams Na 2 C0 3 -H 2 (molecular weight 124) " monohydrated " == 
3.71 grams Na 2 C0 3 (molecular weight 106) really " dry." 

The sodium chlorid-sodium carbonate solution should be made 
up in distilled water and filtered. If the salts used are pure and 
the whole is properly prepared the resulting solution is perfectly 
clear. 

Rectal Injection of the Solution. 

Unless the patient is mentally incapable of comprehending 
what we say, it is well to explain to him before an injection is made 
just what we desire to accomplish and so secure his cooperation. 
As the solution is hypertonic and contains alkali in addition, it not 
only irritates the rectum somewhat, but leads temporarily to a 
secretion of water into the rectum while the salt and alkali are 
being absorbed. 1 The patient, in consequence, has a desire to go 
to stool, which after we have once permitted him to satisfy, we 
wish him to overcome. By obtaining his cooperation, the solution 
is retained for longer periods of time, or entirely, and correspond- 
ingly we get a more perfect absorption of the alkali and salt. 

To inject the solution we may make use either of a con- 
tinuous drip method, or inject larger quantities at varying 
intervals of time. It is not necessary first to cleanse the rectum 
locally, and especially are we not to try to accomplish this end 
by a previous administration of cathartics. These methods 
only increase the irritability of the rectum. It is well, of course, 
if the lower bowel is empty (as immediately after the patient 
has had a stool) . But if no movement has occurred recently 
we make our injection just the same. Perhaps the patient will 
then have a stool from the alkali-salt solution injected. This 
cleans the rectum, and we begin again. 

For administration of the alkali-salt solution the patient 
should first be comfortably arranged in bed. He should lie on 

1 No solution is absorbed or secreted "as such." See page 318. 



682 



(EDEMA AND NEPHRITIS 



C 



his left side on a rather hard bed and with no 
pillow, or only a small one, under his head. His 
hips may be elevated slightly to give still greater 
pitch to the rectum, but this should not be at- 
tempted unless the patient can be made perfectly 
comfortable. 

We are now ready to inject the solution, and 
may choose either the slow drip method or the 
fractional instillation method. The choice from 
the patient's point of view is about evenly divided 
between the two, and he should be consulted and 
his wish followed. 

The fractional instillation method will be de- 
scribed first. For this the apparatus shown in 
Fig. 209 may be used. A is a funnel that has a 
capacity of not less than 250 cc. B is a soft rubber 
tube at the lower end of which is the pinch clamp C. 
D is a short glass tube that connects B with the soft 
rubber catheter or rectal tube E. The solution to be 
injected is heated to 40° C. (110° F.) and the patient 
being in position, the catheter is lubricated with 
petrolatum. Into the funnel are now poured 250 cc. of Figure 209. 
the solution, and the stop-cock is temporarily opened 
so as to drive the air out of the tube and catheter. The catheter 
is then gently inserted well into the rectum and the funnel is 
emptied by again opening the pinch-cock. The short glass tube 
will inform the operator when the last portions of the mixture 
are flowing into the rectum, when the hold on the pinch-cock 
is released. In this way no air will be allowed to enter the rectum 
and balloon it, and extra irritation from this source is avoided. 
If the patient's lower bowel has been empty, the injection is 
usually easily retained, and may be repeated in half or three- 
quarters of an hour. If the bowel was filled with fecal matter 
the first injection serves to bring on a movement, and the cleared 
bowel will subsequently absorb better. The injections may be 
repeated as often as the symptoms of the patient demand it, 
or until the patient finds them difficult or impossible to retain. 
A period of rest should then be given. If our case is so urgent 
that this cannot be allowed with safety, then the solution must 
be given intravenously (see below). 



NEPHRITIS 



683 



For the continuous drip method the arrangement shown in 
Fig. 210 works well. A is an ordinary half liter or liter graduated 
irrigating vessel with a side tubulation. It connects through 



the rubber tube B, carrying a pinch-cock C, with the glass insert 
7), in which lies a thermometer. The insert connects with 
the soft rubber catheter or rectal tube E. F is a glass insert 
which permits observation of the rate at which the solution is 
dripping into the rectum. From 1 to 4 drops a second should 
enter. This is about as high a rate as the patient can stand 
without rejecting the fluid. Roughly, this corresponds to an 
injection of from 240 cc. to 960 cc. per hour. 

The injection fluid is retained best if it is delivered into the 
patient at not less than body temperature, and 40° C. (110° F.) 
is better. For this reason the thermometer in D, located as 
near the rectum as possible, is of great convenience. As the solu- 
tion slowly passes out of A through the tube, it falls in temper- 
ature. The vessel A is therefore conveniently filled with the 
solution at a temperature somewhat above 40° C. Or one can 
set this vessel into a second one containing warm water, or place 
the tube B in warm water, or cover it with a blanket by way 
of maintaining the solution at a proper temperature as con- 
venience and the ingenuity of the medical man dictate. 

In hospital practice, thermostatic devices heated by electricity 
or gas may be conveniently installed. 

Amount and Time Interval. 
How much of the solution may be given by rectum and how 
^ong do we continue with it? The answer to this is found in the 




Figure 210. 



684 



OEDEMA AXD NEPHRITIS 



condition of the patient. So far as I have been able to observe, 
no harm can be done by indefinite use of the solution. A full 
physiological effect is obtained when the patient is kept free from 
the various signs and symptoms of nephritis, and the urine is per- 
sistently neutral in reaction toward litmus. Such a reaction of the 
urine may be obtained in a few hours or it may take all day. 
It all depends upon the initial content of acid in the patient's 
body and the rapidity with which the alkali is being absorbed. 
A call for two to four liters in the twenty-four hours is none too 
much. Where a neutral urine is not obtained the efficacy of the 
therapeutic measures employed must be taken under review. If 
adequate and the patient can not be alkalinized the prognosis 
is bad irrespective of the nature of the pathological circumstances 
producing the acid intoxication. The symptoms may have 
cleared entirely even before the saturation of the body with alkali 
has been carried to the point where the patient secretes a persist- 
ently neutral urine. It is, however, unsafe to stop short of such 
a point or to allow the patient to swing back to the even normally 
acid side too early. 

Individuals differ greatly in their behavior toward these injec- 
tions. I have seen patients bear them for weeks at a time with- 
out complaining, and without ever rejecting them. Others will 
insist from the first that they cannot hold them. A few quieting 
words of explanation to the patient help much. It is well to point 
out that if these hypertonic salt-alkali mixtures are retained for 
any time at all, say even for an hour, they do much good. When 
at the end of such a period the patient rejects some fluid from the 
bowel, this is not the same as that which was introduced, simply 
minus a certain quantity that has been absorbed. Hypertonic 
sodium chlorid-sodium carbonate mixtures are not absorbed as 
such. The salt and alkali are absorbed out of the solutions while 
water is being secreted into the bowel. Therefore,- if the solution 
is retained even for a short time, the patient will have increased 
his body-content of alkali and salt, which is the whole purpose of 
the therapy. 

After the kidneys are functioning in a more normal way we 
may substitute for the hypertonic sodium chlorid solution one 
more nearly isotonic with the body fluids. A solution of sodium 
bicarbonate containing 12 to 14 grams to the liter of distilled 
water does very well. This is about equal in concentration to a 
" physiological" sodium chlorid solution and preferable to it, for 



NEPHRITIS 



685 



while not as powerful as the carbonate, sodium bicarbonate 
neutralizes acids stronger than carbonic and so helps to maintain 
the neutral reaction of the urine. Sodium bicarbonate may be 
injected in indefinite amounts without giving rise to rectal irrita- 
tion. I use it much on this account in children and in protracted 
nephritides in adults, where I frequently raise the concentration 
to 18 or 20 grams to the liter. 

The desire to introduce into the nephritic the bivalent metals 
which dehydrate the body colloids far more than do the uni- 
valent metals cannot be easily satisfied. The reason for this is 
obvious. Their carbonates and hydroxids are largely insoluble, 
and so the administration of bivalent metals such as calcium 
or magnesium along with carbonates or hydroxids is impossible. 
The only schemes that I have found of service are limited to 
patients with mild nephritis and to those recovering from the 
severer types, where lime water may be added to the milk con- 
sumed by the individual, or he be given magnesium oxid, milk 
of magnesia, and soluble calcium or strontium salts by mouth. 
For rectal injection a " physiological," 0.85 per cent sodium 
chlorid solution, to which 0.1 per cent calcium chlorid is added, 
also works well if alkaline solutions have not been used for 
some hours previously. 

It is well here to consider the effects of the sweating so com- 
monly practiced in nephritis. It has been used so long and with 
such good results that its usefulness cannot be doubted, and 
yet I question whether what it accomplishes is really correctly 
understood. For the most part sweating (as purging) is sup- 
posed to act as a partial or complete substitute for kidney 
function, it being held that with the sweat, poisonous substances 
which should be eliminated through the urine are carried off 
through the skin. Since the sweat chemically contains much 
the same sort of material as urine, this belief is, of course, partly 
justified, but even with copious sweating we get in the aggregate 
but little through the skin. Sweating is an effective method of 
dehydrating the swollen body colloids and the relief of coma, of 
headache, of high blood pressure due to cerebral cedema, of 
vomiting and Cheyne-Stokes respiration and of a generalized 
cedema, together with evidence later of a better urinary secre- 
tion (following dehydration of the swollen kidney) a better 
general circulation, etc., are more logically explained through 
this dehydration than on the older basis which held that " nephri- 



686 



(EDEMA AND NEPHRITIS 



tic toxins " assumed to be responsible for these various signs 
are thus lost vicariously through the skin. Sweating dehydrates 
all the organs of the body and permits a better circulation to 
take place through them. 

It is self-evident how sweating may relieve a swollen kidney 
and how in the end it therefore accomplishes what alkalinization 
and increase in salt concentration are trying to do. Only in 
sweating two things must be kept in mind. While it is true that 
by this means we dehydrate the body tissues, sweating does 
nothing to meet the causes for the increased colloid swelling. 
Second, when we carry off water through the skin (or bowel) 
we must not expect the same water to be able to come through 
the kidney. Diuresis follows sweating only secondarily. Only 
when after the shrinking consequent upon the sweating a better 
blood supply has been assured the kidney may this recover 
sufficiently to be able to put out later water brought to it in a 
" free " state. 

6. The Treatment of Severe Cases of Nephritis 

Under this heading we shall consider those patients in whom 
we encounter such especially alarming signs and symptoms as 
great or complete suppression of urine, rapidly progressing optic- 
nerve changes, persistent headache and nausea, vomiting, con- 
vulsions, stupor and coma, great quantities of albumin in the 
urine, etc. 

While we realize that a complete explanation of the nature and 
of the cause of these various clinical signs cannot be summed 
up in any brief statement, we believe that as previously em- 
phasized, an essential, if not the essential element in all of 
them is an oedema of the affected part. This oedema is represented 
physico-chemically by an increased colloid swelling of the tis- 
sues involved, and as responsible for such, we hold the abnor- 
mal production or accumulation of acid in the part, either 
alone or in conjunction with such other substances as are also 
capable of increasing the hydration capacity of the tissue colloids. 
Or, to repeat, what we call the serious complications of nephritis 
are not really complications secondary to this pathological entity, 
but are manifestations in other organs of the body, of the thing which 
in the kidney we call nephritis. 

Just as the nephritis is in large measure an oedema of the 



NEPHRITIS 



687 



kidney, so the optic nerve swelling and the " retinitis " of nephritis 
are oedemas of the optic nerve and of the retina; the headache, 
convulsions, and coma are manifestations from an oedema of 
the brain, the persistent nausea and vomiting of central origin, 
manifestations from an oedema of the medulla; the generalized 
oedema, an expression in the body tissues of what in the kidney 
we call nephritis. The same intoxication or the same vascular 
disease, underlies all these changes, and it is a mere accident 
that one nephritic will show particularly prominent eye symp- 
toms, another a great generalized oedema, while a third will 
call us to his side by a convulsion. For any one of a number 
of reasons, the oedema may become particularly prominent 
in his optic apparatus, or in his body tissues generally, or in 
his brain. If we bear these facts in mind, it will serve to indi- 
cate why T believe that any or all of these signs demand the 
same general treatment, and why, when we succeed in com- 
bating a particularly prominent one, we find that we have suc- 
ceeded in combating all the rest as well. 

Whether the particularly alarming symptoms spring from 
the kidney itself (a suppression or urine, a great albuminuria, 
etc.), or whether they spring from the brain (convulsions, stupor, 
coma), the eye (" papillitis," " retinitis," partial blindness), or 
the medulla (nausea and vomiting), the purpose of our therapy 
is the same — we wish to stop and reduce the swelling of the 
involved tissues. 

Naturally the best and quickest way to do this is to inject 
something into the blood, and what this something must be we 
have already discussed. 



Preparation of an Alkaline Hypertonic Salt Solution 
for Intravenous Injection 

The following formula, already recommended above, does 
very well: 

Sodium carbonate (Na 2 C0 3 • 10H 2 O) 10 grams 

Sodium chlorid 14 grams 

Distilled water, enough to make 1000 cc. 

It is well to have this solution ready for immediate use, for 
its preparation in sterile form takes time, and need for it when it 
arises is urgent. What we have said regarding chemicals holds 
here also. Only chemically pure salts and freshly distilled 



688 



(EDEMA AND NEPHRITIS 



water are to be used. The crystallized sodium carbonate con- 
taining ten molecules of water of crystallization is recom- 
mended. If some other form of the salt is used, less than 10 
grams to the liter are to be used, as discussed on page 681. 

The finished solution as injected into the patient must be per- 
fectly clear and sterile. Simple as it would seem to be to obtain 
this result, it is not always secured even when its preparation 
is left to trained helpers. Therefore, I may be pardoned for 
detailing the following rules for its preparation in containers that 
make it available for immediate use. 

Trouble arises from the fact that alkaline solutions cannot 
long be kept in contact with ordinary glass containers without 
reacting with the glass and so leading to a separation of insoluble 
silicates. High-grade glass flasks resist better than other material, 
and so the finished solution may be sterilized and kept in these. 
For this purpose, it is only necessary to dissolve the sodium 
chlorid and the sodium carbonate in the necessary amount of 
freshly distilled water and filter the solution through moistened 
filter paper (in order to get no shreds into the solution) into 
the thoroughly cleaned flasks. It is convenient to have two liters 
of solution in each flask. The flasks are stoppered with gauze- 
wrapped cotton stoppers, and may be sterilized in the ordinary 
way by boiling. This scheme works well in hospitals or anywhere 
where storage room is plentiful. 

When needed for injection, this solution may then be poured 
into any one of the properly sterilized intravenous injection 
apparatuses that abound in the market. If the solutions show 

a precipitate in spite of the use of good 
glass containers, the clear solution may 
be decanted or the whole may be fil- 
Figure 211. tered through a sterilized funnel into the 

neck of which has been forced a little 
sterile glass wool. Or a sterilized glass bulb insert of the type 
shown in Fig. 211, into which has been forced some glass wool 
may be used in the delivery tube of the injection apparatus. 
As the carbonates and hydroxids of the polyvalent metals are 
all insoluble, every piece of any injection apparatus must be 
rinsed and sterilized only in distilled water. When ordinary tap 
water is used calcium and magnesium precipitates cloud the 
injection mixture. 

In my own experience I have found it convenient to make 




NEPHRITIS 



689 



up the sodium chlorid-sodium carbonate solution in concen- 
trated form in ampoules, and then mix this with enough freshly 
distilled water to yield the proper injection mixture at the time 
it is needed. One proceeds as follows: 

Any desired number of multiples of 10 grams of sodium car- 
bonate (Na2C03 -10H 2 O) and 14 grams of sodium chlorid are 
dissolved in enough water to make 60 cc. of finished solution. 
This solution is filtered and then sterilized by boiling. 1 One or 
more ampoules of the type shown in Fig. 212/ A, and of about 
60 cc. capacity (if these are not available, bottles will do as well) 
are thoroughly cleaned, rinsed in distilled water, and then boiled 
in distilled water to sterilize them. Into each of these is then 
filtered through a small sterilized funnel plugged with glass wool, 
60 cc. of the concentrated sodium car- 
bonate-sodium chlorid mixture. When 
the ampoules have been filled, they are 
sealed in a flame, as in Fig. 212. B. 
If bottles are used they are stoppered 
with sterile rubber or paraffined corks, 
and over these is fastened a sterilized 
paper hood to protect the necks from 
contamination. When an intravenous 
injection is to be given, an ampoule is 
taken, its neck is nicked with a file, 
and this and the lateral bead are cleaned 
with alcohol, and broken off. The con- 
tents are then poured into 940 cc. of 

freshly distilled water, care being taken to mix the whole so that 
the specifically heavier salt solution may not simply settle to the 
bottom. 

After many trials I have found these the best ways to proceed, 
and as dispensing pharmacists in any community are willing to 
carry ampoules as here described in stock, one can easily obtain 
fresh and clean solutions at all times. If a precipitate of silicates 
should be found in an ampoule, one can readily avoid pouring this 
into the injection apparatus, or one may filter the contents of the 
ampoule through a little glass wool, 

1 In the first edition of Nephritis and in a paper or two I cautioned against 
the use of excessive heat in sterilizing these carbonate solutions. The cau- 
tion I find was scarcely necessary, for at the ordinary temperatures and 
pressures at which such sterilization is carried out, the carbonate is not 
decomposed. 



A B 
Figure 212. 



690 



(EDEMA AND NEPHRITIS 



Technic of the Intravenous Injection of the Solution. 

My experience has convinced me that it is best in making these 
intravenous injections to cut through the skin and expose clearly 
to view the vein to be used. The results are bad if one fails in 
his attempt to enter a vein with a hypodermic needle through the 
skin. The salt-alkali mixture produces a great destruction of 
the tissues if it is by accident injected into them. Under no 
circumstances must such salt-alkali mixtures ever be given sub- 
cutaneously, under the breast, or intramuscularly. 1 

A vein that is deemed sufficiently large is sought in the arm, 
in the leg, or, if necessary, in the neck. As we may wish to make 
several injections it is advisable to pick for the first injections the 
prominent veins most distant from the heart. Unfortunately in 
many of the conditions in which we wish to use the sodium 
chlorid-sodium carbonate solution, not much choice is allowed, 
for the blood vessels are so much contracted (toxemic shock?) 
that it is often impossible to find any usable vein below the bend 
of the elbow. Even here surgeons have been unable to find 
the median basilic in such cases. This will explain to the reader 
why in extreme cases such a vein as the jugular needs to be and 
has been used. 

To expose the vein painlessly a few drops of a cocain or novo- 
cain solution may be injected into the skin. If the patient is 
stuporous or in coma this is, of course, needless. The vein is 
freed from its surroundings and a ligature is tied about its distal 
end. A second ligature is thrown about the vein and after a cut 
has been made into the vein and the cannula connected with the 
injecting apparatus has been inserted, this second ligature is 
tied. Of course, care is taken to have no air enter the vein. 
The best type of cannula to use is shown in Fig. 213. The 

two openings ■ at the tip and 
laterally make it well-nigh im- 
possible to shut off the infusion 
stream by crowding the cannula 
against the vein wall. The taper- 
Figure 213. mg character of the cannula 

allows one to push it into even 

1 Men who have failed to heed this oft-repeated caution of mine have 
been severest in attacking my teachings. Is it too much to ask critics at 
le^st to read what one has written? 




NEPHRITIS 



691 



a small-calibered vein, and the corrugation holds the cannula in 
place when the second ligature is tied. 

Sometimes it is better to use a large hypodermic needle in 
place of the cannula. The first ligature about the exposed vein 
then serves to steady the vein when the needle is pushed into it. 
When the hypodermic needle is used it is simply held in place 
until the injection is completed. As can easily be imagined, 
the use of the needle is especially convenient when one works with 
such a vein as the jugular. The disadvantages in its use arise 
from the fact that one is likely at any time to injure the blood 
vessel if the patient moves, and from the further fact that the 
carbonate solution affects the coat of the vein and so tends to 
leak out about the needle after the injection has been kept up 
for some time. 

The medical attendant should choose for intravenous injec- 
tion the apparatus with which he is most familiar. 

Perhaps that shown in Fig. 210, with a cannula replacing the 
catheter, and minus the thermometer and the insert F, is the 
simplest available form. The side tubulation with the rounded 
bottom, or a glass bulb insert filled with glass wool (Fig. 211) 
will make it almost impossible, if care is used, to inject any 
sediment that may accidentally appear in the injection fluid. 

The pressure bottle arrangement shown in Fig. 214 possesses 
some advantages over the apparatus just referred to. No special 
comment is necessary re- 
garding its use, and we 
need not in this day em- 
phasize the necessity of 
having all rubber tubes, 
etc., perfectly sterilized by 
boiling in distilled water. 

The faults of the ap- 
paratus shown in Fig. 214 
are that it possesses no 
arrangement for keeping 
the solution at body tem- 
perature, and that we do 
not know in as accurate a 
manner as we desire, the 

exact rate and the exact Figure 214. 

pressure at which the sodium 




692 



(EDEMA AND NEPHRITIS 



chlorid-sodium carbonate solution is entering the patient at any 
moment. To meet these difficulties, the useful apparatus shown 
in Fig. 215 was devised by Edmund M. Baehr. We have here 
again the glass pressure bottle shown in Fig. 214, but it is now 
surrounded by a copper water jacket by means of which the 
injected fluid may be kept at body temperature or a little above. 
The thermometer registers the temperature existing in the jacket, 
and as the temperature of the injection fluid falls on its way 
into the patient, it is advantageously kept a little above that 
at which we wish to deliver the solution into the patient. The 
rubber bulb in Fig. 214 is advantageously replaced in the appa- 
ratus shown in 'Fig. 215, by a metallic pump. A mercury 
manometer, inserted as indicated in the drawing, " allows one 

to know at all times the exact pressure 
obtaining in the pressure bottle. 

One needs at all times to inject 
the solution slowly into the circulation 
so that it may mix with the blood, 
and at as even a rate as possible. 
Not over 30 to 40 cc. should be in- 
jected per minute. By testing out 
the apparatus before making the 
injection one can easily note just how 
much pressure is necessary to accom- 
plish this. As the pressure in the 
larger veins is almost nil, 30 to 40 
mm. of mercury pressure usually 
suffice, and one need never run 
Figure 215. above 50 mm. if a cannula or needle 

of proper diameter is chosen. If we 
give the solution to a patient who for any reason has to maintain 
an upright position, it is well to remember that in such a case 
the arm must be comfortably supported in as horizontal a posi- 
tion as possible in order not to have to work against a consider- 
able hydrostatic pressure in the veins. The pressure and the 
oscillations of the mercury column tell us every moment whether 
our solution is flowing in properly or not. 

The Quantity and Time Interval of the Salt- Alkali Injections 

It is necessary to say now how much of the solution may be 
injected at one time and how often the injection may be repeated. 




NEPHRITIS 



693 



In any suppression case or in a case with convulsions, per- 
sistent vomiting or other alarming symptoms, 1800 to 2000 cc. 
of the solution should be given for the first dose. In the case of 
a child we give a proportionate dose obtained by dividing the 
child's weight by that of a small adult. A 30-kilo (66-pound) 
child gets half the dose of a 60-kilo (132-pound) man, etc. The 
repetition of the injection and the amount given subsequently 
must then be determined by the condition of the patient. If, 
within two or three hours, urine begins to come and the convul- 
sions stop, or if the sensorium clears or the headache and eye 
symptoms improve, then we know that we have given enough 
for the time being. 

If the patient is awake, he is likely to complain of thirst 
during the hour that we are making the injection. It is best 
not to let him satisfy this immediately, for we wish to get as 
great a shrinking effect of the salt and alkali upon his various 
organs as possible. But there is no objection to his moistening 
his mouth, and at the end of four to eight hours, if his alarm- 
ing symptoms seem to be under control, we are only too glad 
to have him drink. Only we must always remember that as 
soon as water is given we decrease the patient's salt concentra- 
tion, and if his kidneys are functioning, we are actively wash- 
ing salt out of the body. So, to carry along our therapy, we 
give a natural or artificial alkaline water instead of plain water 
by mouth, and with this we may give various salts. By thus 
giving alkali and salts by mouth or by using alkali and salt 
by rectum, we may now be able to keep our patient growing pro- 
gressively better. But if this is not the case, or if the redevel- 
opment of some prominent sign or symptom informs us that our 
patient is relapsing into his, previous state, then we may give a 
second injection of one or even two liters of solution, six, twelve, 
or twenty-four hours after the first injection. Closer rules than 
this can hardly be given. If our patient improves for a number 
of hours after the first injection, and then goes down again, we 
repeat the injection at this time; 500 to 1500 cc. in any twenty- 
four hours after the first injection is certainly safe. 

If the suppression of urine is not absolute, then it is a useful 
guide to the amount of alkali and salt that may be urged upon 
the patient. It is safe to give alkali and it should be given until 
the urine is persistently neutral to litmus. For self-evident reasons, 
it is possible for the urine to be alkaline immediately after 



694 



(EDEMA AND NEPHRITIS 



an intravenous injection, even when the acid content of the 
body generally is still abnormally high. Not until the urine 
is persistently neutral and is held there are we really succeeding 
in getting an adequate amount of alkali into the patient. 

Various observers have commented on the large quantity 
of fluid that is injected intravenously in clinical cases of neph- 
ritis and allied conditions. I have injected as high as 6 liters 
(6 quarts) in twenty-four hours. Some clinicians have for various 
reasons remonstrated that this is dangerous, chiefly because 
they hold such injections to " increase the blood pressure." 
Observation is better than guessing in settling such points. 
Measurement made just before and just after a two-liter intra- 
venous injection shows either no change whatsoever in the 
blood pressure, or, if it has previously been high, a fall. 1 Others 
hold such injections to " throw work on the heart." In so 
far as the elimination of water from the body costs energy, 
this is to a limited extent true, but only to a very limited extent, 
as I have previously insisted. Physiologists know that the 
volume of the circulating blood can be more than doubled without 
appreciable effect. Counting the blood in the human being as 
one-thirteenth the body-weight, it is therefore entirely safe to 
inject a liter of fluid for every 13 kg. (about 28§ pounds) of body- 
weight; but as pointed out previously, this is a safe figure 
if blood, in other words, water in combination with a colloid, 
is injected. Only such remains in the blood vessels. When 
the water is injected " free," as in a salt solution, this rapidly 
leaves the blood vessels, and so the amount of this that may 
safely be injected lies still higher. What I have said here 
is still largely true even when we deal with sclerosed blood 
vessels, though to allow for the diminished elasticity, a slower 
injection or injection of a less amount at more frequent inter- 
vals, as the judgment of the operator may dictate, may advan- 
tageously replace the single large injections. 

About one in every three patients injected with alkaline 
hypertonic salt solution develops some reaction. At times he 
develops a chill which, however, does not last long, or he has a 
slight rise in temperature. 2 Once I found sugar in the urine. 

1 James J. Hogan: Lancet-Clinic, 113, 6 (1915). I 7 " 

2 See in this connection Rollin T. Woodyatt, J. O. Balcar and W. D. 
Sansum: Arch Int. Med., 24, 116 (1919). 



NEPHRITIS 



695 



It will be noticed that these findings are similar to those observed 
after intravenous injections of salvarsan and other medicaments. 
European authors have laid stress on the distilled water employed 
in making up the solution, maintaining that bacterial products 
are present in old distilled water. For this reason I have always 
urged the use of freshly distilled water, but even then I have 
seen these reactions. I next attributed the effect to the action of 
the alkali on the red blood corpuscles, and a resulting hemolysis. 
This, however, can only be a small part of it, for one of the 
worst reactions I ever saw occurred in a woman to whom I 
gave a concentrated solution of neutral salt only. To explain 
the findings I have come to the tentative conclusion that two things 
are active: first, a shrinking of the red blood corpuscles which 
makes these less able to carry oxygen; second, a more important 
direct action of the salt and alkali on the medulla. The latter 
effect I think, leads to the vasomotor disturbance in the skin 
which we call a chill, to the consequent retention of heat that 
accounts for the rise in temperature, and to the appearance of 
sugar in the urine, as C. Bock and F. A. Hoffmann 1 found many 
years ago when rabbits were perfused with sodium chlorid solutions. 
How to avoid these effects is not yet entirely clear. The rules 
I have formulated for my own guidance call for the use of 
freshly distilled water and as slow an injection as is conveniently 
possible. It is undoubtedly better to give in place of single 
large intravenous injections several smaller ones separated by 
intervals of time which allow the salt and alkali to diffuse into 
the body-tissues, but unfortunately the necessity of opening 
into more than one vein and the critical condition which we are 
usually asked to meet does not always allow of this. Before, 
throughout and after the injection the patient is carefully pro- 
tected from muscular exertion, and the possibility of a chill is 
guarded against by extra blankets, hot-water bags, etc. If 
complete muscular and mental relaxation is not easily obtained, 
a small dose of codein, heroin or morphin may be used. 

Perhaps the way to proceed is best illustrated by abstracting 
a few clinical experiences and commenting upon them directly. 

1 C. Bock and F. A. Hoffmann: Arch. f. (Anat. u.) Physiol. (1871). 
Martin H. Fischer: Univ. of California Publications in Physiology, 1, 
77 (1903); 1, 87 (1904); Pfliiger's Arch., 106, 80 (1904); 109, 1 (1905)! 



696 



(EDEMA AND NEPHRITIS 



7. Clinical Abstracts and Comment 

§1 

The credit of having been the first to utilize upon patients 
the principles outlined in this volume belongs to James J. Hogan. 
Since then others of my friends and colleagues have used alkalies, 
salts, and water for the relief particularly of the acuter neph- 
ritides, and their accompanying manifestations, and with favorable 
results. My thanks are due them all for permitting me not 
only to see many of their patients with them but to use the 
facts contained in the brief illustrative histories that follow. 

Case VII. — Mr. G. B., a laborer, aged twenty-four years, and previ- 
ously in good general health, was operated upon under ether at 9 p.m., 
February 15, 1912, for a right inguinal hernia of several years' standing. 
The operation was a long one. Examination of the urine before opera- 
tion had been negative. Nothing abnormal was noted except that 
vomiting was rather severe after the operation, continuing until late 
in the afternoon. At this time, in response to inquiry the patient said 
he had no desire to urinate. The same condition existed late that night, 
even though by this time the patient was swallowing and retaining con- 
siderable quantities of water. The following morning the patient was 
catheterized, and 20 cc. of brownish, viscid liquid heavily charged with 
albumin were obtained. Through the day he was given hot drinks 
and hot fomentations over the kidneys, but no spontaneous voiding 
occurred. At 9 p.m., that is to say, eighteen hours after the operation, 
he was again catheterized, and 15 cc. of urine of the previously described 
character were found. At this time liquid by mouth was stopped and 
administration of the following solution by slow drip into the rectum 
was started: 

Sodium carbonate (Na 2 C0 3 - 10H 2 O) 10 grams 

Sodium chlorid 14 grams 

Distilled water, enough to make 1000 cc. 

The patient retained the solution well, and by 10.30 had taken up 
the whole liter. At 11.45 he asked for a urinal, and passed 180 cc. of 
highly albuminous urine filled with casts and red blood cells. At 1 a.m. 
he passed another 160 cc, and at 3 a.m. 205 cc. The urine by this 
time was almost as clear as water. 

As he felt thirsty, a glass of water was now permitted him every hour. 
The urinary output continued so that by 9 p.m. of February 16, that is to 
say, in the first twenty-four hours after the drip was started, 2350 cc. 
were voided. By the evening of this day the albumin had dwindled to 
a trace, and only occasional granular casts could be found. 



NEPHRITIS 



697 



In the following two days, during which 2470 and 2385 cc. respectively 
of urine were obtained, these signs disappeared entirely. The urine of 
this patient, who is entirely well, has been examined repeatedly since, 
with negative results. 

Case VIII. — Mrs. M. L. T., aged forty-seven years, a laundress, was 
operated upon under ether for an extensively broken pelvic floor with 
prolapse of the uterus, at 8.30 a.m., July 1, 1912. She had not been 
in good general health previously, though she complained of nothing 
specifically excepted her uterine condition. Urinary examination on 
admittance to the hospital the day previously had shown a trace of 
albumin and occasional casts, but the general condition of the patient 
did not seem sufficiently bad to contraindicate an operation which was 
much needed. Her condition after the operation was fair, but she did 
not urinate. Catheterization twelve, twenty, and twenty-eight hours 
after her return from the operating room was dry. At 9 p.m., July 2, 
when catheterization was again found to be dry, she was slowly injected 
intravenously with 1600 cc. of the following mixture: 

Sodium carbonate (Na 2 C0 3 - 10H 2 O) 20 grams 

Sodium chlorid . 28 grams 

Distilled water enough to make 2000 cc. 

She was catheterized at 3 a.m., when 90 cc. of a viscid, brownish 
urine, filled with albumin and casts, were obtained. The urine was 
highly acid to methyl red. 1 At 7 a.m. another 90 cc. of a similar looking 
urine were obtained. Because of the perineal operation, rectal injec- 
tion of alkali and salt was not urged, but half a glass of Vichy water, 
with a powder of half a gram each of sodium bicarbonate and magnesium 
oxid, was given every hour. On this regime 420 cc. in all of brownish, 
highly albuminous urine filled with casts were obtained in the first 
twenty-four hours after the intravenous injection. This alkali therapy 
was continued. The urine became neutral to litmus and remained so 
after July 5. In her second twenty-four hour period she secreted 670 
cc. of urine, and in the third, 1140. The urine became clearer, the casts 
fewer, and the albumin content diminished steadily (from 9 grams to 
the liter in the first specimens to 1.5 grams on July 5 and 6). Her 
further history is summarized below : 



For 24-hour period of 


Amount of urine. 


Grams of albumin 
per liter (Esbach). 


July 7 


1790 


1.0 


July 8 


2100 


0.8 


July 9 


1873 


0.9 


July 10 . 


1840 


0.5 



1 The advantages of using methyl red and paranitrophenol as indicators 
instead of the ordinary litmus are explained on page 774. 



698 



(EDEMA AND NEPHRITIS 



Numerous hyaline and granular casts were found in all these specimens. 
These continued with a urinary output of 1700 to 2200 cc. per twenty- 
four hours, containing albumin that varied little from half a gram per 
liter until she was discharged from the hospital July 21. 

A more detailed physical examination after her operation than had 
previously been possible, showed this patient to have easily palpable 
peripheral blood vessels with an evidently enlarged but regularly beating 
heart. The systolic blood pressure was 165 mm. of mercury, the diastolic 
140. Tender bones with bogginess of the tibial periosteum, a tender 
nasal bridge, vague night pains, and three miscarriages for which no 
cause was assigned, together with the casts and albumin found on admis- 
sion to the hospital, led to the diagnosis of syphilitic vascular disease 
with cardiac hypertrophy and involvement of the kidney (chronic 
interstitial nephritis) . 

Since leaving the hospital this patient has been seen occasionally. 
Some albumin and casts are constantly found in the urine, and her blood 
pressure continues at approximately 160 mm. The patient herself 
complains of nothing and feels herself improved by her operation. 

In the light of our considerations it is not surprising that an 
anesthesia nephritis as illustrated in these two cases is easily 
relieved by alkali and salt. During an anesthesia we introduce 
into the body a poison which interferes with the normal oxida- 
tion chemistry of the cells and that we have an abnormal pro- 
duction and accumulation of acid following this, is attested 
not only by the thirst of which the patient complains, but by the 
accelerated breathing and heart beat, the abnormally high acid 
(hydrogen ion) content of post-anesthetic urine, and the appear- 
ance in it of such " acidosis " products as acetone, diacetic 
acid, lactic acid, etc. But as soon as we stop administering the 
anesthetic the patient begins to exhale it, and so in a compara- 
tively short time the intoxication responsible for the abnormal 
production and accumulation of acid disappears. 

The patient also usually succeeds in oxidizing the acid products 
resulting from his intoxication, and so it is the usual thing to see 
him bear his anesthesia without bad after-effects. But some- 
times he is not so successful and then if his intoxication evidences 
itself chiefly from the side of his kidneys, we say he has a post- 
operative nephritis. (If it should happen to involve his liver 
particularly, we say he has a " postoperative jaundice," a " chloro- 
form liver," etc.). There is nothing surprising about the fact 
that an administration of alkali and salt relieves this condition. 
The alkali neutralizes the abnormal acids present, and the 



NEPHRITIS 



699 



increased salt concentration reduces the hydration capacity of 
his swollen kidney (and other body) colloids. If the injury to 
them has not been too great (or technically put, if the colloid 
changes characteristic of nephritis have not become "irreversible"), 
these measures quickly restore his kidneys (and other involved 
organs) to a more normal state. As the kidney shrinks, a better 
blood supply to the organ is obtained, and so the kidney cells 
are once more enabled to resume their work. Once this result 
has been obtained a recurrence need scarcely be feared, for the 
original intoxicant (the anesthetic) has by this time disappeared 
from the body, and so the relief obtained is permanent. 

What has just been said applies in my judgment to Case 
VII. In Case VIII the problem is essentially the same, only the 
anesthesia intoxication is this time added to the effects of a blood- 
vessel disease which in itself has already led to the signs of a 
nephritis. The effects of the anesthesia intoxication could, 
as in Case VII, be overcome, but an injection of salt and alkali 
does not remove an endomesarteritis with its effects upon parts 
or all of the kidney, and so casts, albumin, etc., continue to be 
found in the urine even after the suppression following the 
anesthesia has been relieved. 

§2 

If we will write the name of any other intoxicant in the place 
of anesthetic in these considerations, we have what happens, to 
my mind, in the nephritides that we encounter in any of the 
acute infections, and in the various other acute intoxications 
which we know to be associated with the development of neph- 
ritis. Here again nature herself takes care of the great majority 
of cases, but when she does not, we may again be able to relieve 
the urinary condition by alkali, salts, and water. Such a situa- 
tion is illustrated in Case IX, where an unknown intoxicant 
led to suppression of urine and in cases X and XI, where the 
suppression followed scarlet fever. 

Case IX. — (Dr. Elizabeth Campbell, Cincinnati, Ohio.) A. H., 
a girl, aged three and one-half years, had never been ill previously. 
When first seen she was extremely nauseated and vomiting. There 
was a slight general oedema, and her urinary output was low. The 
urine contained much albumin and casts. Enemas of 0.85 per cent 
sodium chlorid solution and calomel by mouth improved the child's 
condition, and brought up the urinary output. Five days later the 



700 



(EDEMA AND NEPHRITIS 



mother reported that since two in the afternoon of the day before the 
child had passed no urine. The child was given hot baths and sweated 
several times. Several 0.3 gram doses of sodium bicarbonate were 
given by mouth, and water was urged. The child had vomited once. 
She was extremely quiet. Temperature and respiration were normal. 
The pulse was 76. 0.2 gram calomel was given at night, and through 
the night hot alkaline drinks, blanket sweats, and enemas of 0.85 per 
cent sodium chlorid solution were continued. The anuria persisted. 
This scheme of treatment was kept up through the following day also. 
The general oedema had in the meantime increased, the patient was 
vomiting, and had grown stuporous, and the pupils reacted slowly. 
In consultation in the early evening of this the third day of the anuria 
it was decided to try the administration of an alkaline hypertonic sodium 
chlorid solution. As it was thought there might be some urine in the 
bladder, the child was catheterized. A teaspoonful of bloody urine 
was obtained. At 9 p.m. 320 cc. of the following solution were injected 
into the rectum by slow drip, the child retaining all of it. 

Sodium carbonate (Na 2 C0 3 • 10H 2 O) 15 grams 

Sodium chlorid 14 grams 

Water, enough to make 1000 cc. 

The child had a restless night. At 5 a.m. she passed 96 cc. of urine 
that looked like pure blood. This was sixty-three hours after the 
suppression was first noted. At 6.15 a.m. another 130 cc. of bloody 
urine were passed; at 7.30, 256 cc, with only a slight amount of blood. 
At 10 a.m. a large voiding was lost with a watery stool. An hour later 
250 cc. of the above alkaline hypertonic sodium chlorid solution were 
slowly injected into the rectum. Through the afternoon the nurse 
reported that " the urine came in an almost steady stream." The 
albumin content of the urine fell rapidly, so that by the following day 
only a trace could be found, and on the fourth day later it disappeared 
entirely. The general oedema disappeared rapidly, and was about 
gone on the third day after the urinary secretion became reestablished. 
•Recovery has been complete. 

Case X. — (Dr. James J. Hogan, San Francisco, California. Mrs. 
. W., twenty-two years old, had passed through a scarlet fever. Dr. 
Hogan was called in consultation on the evening of March 11, 1911, 
and found the patient unconscious with practically a complete suppres- 
sion of urine that had lasted for twenty-four hours. The unconscious- 
ness had lasted for twelve. The following formula was given by the 
continuous drip method into the rectum : 

Sodium carbonate (Na2C0 3 • 10H 2 O) 20 grams 

Sodium chlorid 14 grams 

Distilled water, enough to make 1000 cc. 

The urinary flow recommenced after four hours; on the following 
day her mind had cleared, and the patient made a subsequent uneventful 
recovery. 



NEPHRITIS 



701 



Case XL — (Dr. H. Kennon Dunham, Cincinnati, Ohio.) Master 
M., seven years old, was seen on April 30, 1911, by Dr. Wm. C. Schmidter 
in a rather mild attack of scarlet fever. The temperature at no time 
ran above 101° F. In spite of the apparent mildness of the attack, the 
child developed urinary symptoms. On May 7, when Dr. Dunham 
was first summoned in consultation, a complete suppression of urine 
had lasted for fifty-one hours, the child was conscious, but very stupid, 
presenting a grave picture of intoxication. The eyelids and ankles were 
swollen, the pulse 105, respiration 24. 

At 4.00 a.m. the following mixture was prepared and its injection 
into the rectum begun: 

Sodium carbonate (Na 2 3 - 10H 2 O) 20 grams 

Sodium chlorid 30 grams 

Distilled water enough to make 1000 cc. 

The injection required one and a half hours. About 180 cc. were 
rejected, the remainder of the above solution was retained. Three and 
a half hours after the injection was completed the patient passed invol- 
untarily a large watery stool. Ten hours after the completion of the 
injection he passed a small amount of highly colored urine. Following 
this at short intervals came large voidings of urine which were lost into 
the bed, as the child could not control himself sufficiently to use a bed- 
pan. Not until this, secretion had lasted for four hours could the urine 
be collected. Not counting that which was lost there were collected 
2272 cc. of urine in the first twenty-four hours after urinary secretion 
commenced. The first specimens of urine obtained were so filled with 
albumin as to set into a solid mass on boiling. The amount of albumin 
rapidly decreased, so that during the second day after the injection 
only a moderate reaction for albumin 'was obtained, and on the ninth 
day it disappeared entirely. The intense stupor left the child within 
the first twenty-four hours after injection, and on the third day he was 
actively interested in his surroundings and free from oedema. His 
urinary secretion after being started was readily maintained by the 
milk diet on which he had been from the first and to which alkaline 
mineral water was added ad libitum. 

§3 

For self-evident reasons our prognosis grows worse and our 
efforts need to be greater as the intoxication grows in length or 
becomes of a less removable type. We encounter this situation 
in protracted infections, in acute infections that leave behind 
toxins that stick particularly firmly to the kidney cells (scarlet 
fever?) and in poisonings of this type (phosphorus and the 
metals). Not alone do some of these produce irreversible col- 
loid changes (necrosis) in the cells of the kidney from the start — ■ 
changes, therefore, which can never be " cured " by any thera- 



702 



(EDEMA AND NEPHRITIS 



peutic procedure — but even when such is not the case, in these 
lasting intoxications the interference with the normal oxidation 
chemistry of the kidney cells is of a more lasting character, and 
so our therapy must also be more persistent. A single dose of 
alkali and salt may then do no more than give temporary relief. 
We must meet the intoxication as long as it persists. 

Cases XII, XIII, and XIV may serve in illustration of these 
remarks. 

Case XII. — (Drs. Otto P. Geier and J. L. Tuechter, Cincinnati.) 
G. L., a 34-year-old attorney, developed a severe tonsillitis involving 
both tonsils on May 17, 1911. His temperature was 103.5° F., pulse 
120. The urine was very scanty, highly colored, and contained albumin 
and casts. The next day the patient had intense headache, and in the 
evening became delirious. During these second twenty-four hours 
of his illness he passed but 90 cc. of urine, very smoky in color and 
filled with albumin, red and white corpuscles and casts of all sorts. On 
the third day of his illness he passed no urine at all. His delirium con- 
tinued and his temperature remained at 103° F., his pulse at 124. Iiate 
at night he was given the following mixture per rectum: 

Sodium carbonate (Na 2 C0 3 • 10H 2 O) 20 grams 

Sodium chlorid 14 grams 

Distilled water, enough to make 1000 cc. 

In his delirium most of the first injection was rejected. At 3.00 
a.m., May 20, the injection was therefore repeated. About 500 cc. 
were retained. At 6.00 a.m. 15Q cc. of dark, thick urine were obtained 
which on heating fairly set into a jelly. The urinary secretion became 
more profuse as the day wore on, and in the first twenty-four hours 
after the successful injection 1184 cc. of urine were obtained. As the 
urinary secretion increased, the drowsy delirium passed away, the 
headache disappeared, and the patient volunteered that he felt well. 
The temperature fell to 101° F., the pulse rate to 100. The later speci- 
mens of urine voided in these twenty-four hours after the successful 
injection were clear and amber in color and contained only a little 
albumin, and few casts and blood cells. The rectal injections of 500 
cc. of the above formula w r ere repeated May 21 (temperature 99.5° F., 
pulse 90) and May 22 (temperature normal, pulse 70). Between 
the injections the patient was urged to take as much Vichy water by 
mouth as he could. The urine secreted May 21 measured 1376 cc, 
that secreted May 22, 1408 cc. Some albumin and casts were found 
in the former, only a trace together w r ith some red blood corpuscles but 
no casts in the latter. On May 23 all urinary signs had disappeared, 
and the patient made an uneventful recovery. 

Case XIII. — (Dr. William E. Kiely, Cincinnati.) Three weeks 
before entering the hospital S. C. W., thirty-eight years old, and a mod- 



NEPHRITIS 



703 



erate beer drinker, became short of breath, suffered from headaches, 
and noticed a swelling of his legs and abdomen. Physical examination 
showed no disease of the heart or lungs, but fluid in the pleural and 
peritoneal cavities, with a general oedema of the subcutaneous tissues. 
The urine was low in amount, of high specific gravity, and contained 
much albumin, some blood cells, and hyaline casts. On this a diagnosis 
of {chronic) parenchymatous nephritis was made. After twenty-five 
days of rest in bed, a milk diet, a daily hot bath, saline cathartics and 
digitalis, no improvement in his general condition was noted. There 
was now added to his diet a liter of water daily containing 25 grams of 
sodium chlorid. Improvement in his general signs and symptoms 
began immediately, the urinary output rose, the blood disappeared, 
and the casts and albumin progressively diminished in amount. After 
ten days of this treatment he was much better, and at the end of twenty- 
five all signs of his oedema and the effusions into his serous cavities had 
disappeared. At his own request he got out of bed and began to work 
about the ward, and shortly thereafter left the hospital free of all signs 
and symptoms, except a faint trace of albumin in his urine. In this 
state he has continued up to the present time (that is, for two months 
since leaving the hospital). 

Case XIV. — (Dr. Julius H. Eichberg, Cincinnati.) A. B., a 
40-year-old lawyer, entered the hospital in April, 1911, with a history 
of kidney disease of eight years' standing. At various times during these 
years he had had a diagnosis of chronic parenchymatous nephritis made 
upon him. He had no enlargement of the heart and no increased blood 
pressure. The original cause of the nephritis could not be made out. 
When first seen the patient was passing about 400 cc. of urine per 
twenty-four hours, containing 4 grams of albumin per liter and filled 
with all varieties of casts. On a milk and vegetable diet, sweat baths, 
and saline cathartics his urinary secretion increased somewhat, but 
his general condition did not improve, the number of grams of albumin 
lost each twenty-four hours did not decrease, and his oedema, ascites 
etc., increased. After two weeks in the hospital he had a well-marked 
oedema of his legs, back, chest-wall, scalp, and face. The fluid in his 
abdomen extended to the umbilicus when sitting up. While his general 
hospital regime and diet were kept as before, he now had added to his 
drinking water and consumed each twenty-four hours 7 grams of dried 
sodium carbonate. After ten days of the carbonate administration 
his oedema and ascites disappeared completely, his urine increased to 
approximately 800 cc. per twenty-four hours, though the quantity 
of albumin lost per twenty-four hours did not change perceptibly. 

The patient at this point refused to continue taking the carbonate. 
In five days his weight went up 2\ kilos. The patient was persuaded 
to resume the carbonate, and at the end of another seven days his original 
weight had again been attained, and the visible signs of oedema which 
had developed when the carbonate was discontinued had once more 
disappeared. The urinary output amounted at this time to 800 cc. 
daily, and the albumin dropped to 2.5 grams per liter. 



704 



OEDEMA AND NEPHRITIS 



At this point the patient refused a second time to take the sodium 
carbonate, and again the swelling of his legs and back developed, while 
his weight rose as before, 2\ kilos in less than a week. Following this 
period he returned a third time to the carbonate, and in six days had 
again lost his 2\ kilos and the obvious signs of an oedema. This is his 
state at the present writing when for four months he has been passing 
1280 cc. or more of urine daily, containing some casts and 0.75 gram of 
albumin per liter. He has left the hospital in fair condition, has a 
good appetite, sleeps well, and has resumed the practice of his profession. 



§4 

The nephritides occurring in. the course of pregnancy 1 
constitute a common and important group. How alkali, salt 
and water help in their management is illustrated in Cases XV, 
XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, and 
XXIV. 

1 The origin and nature of the poison which gives rise to the symptoms 
of the pregnancy intoxications form interesting food for speculation. The 
beginning of the intoxication with pregnancy and its prompt cessation with 
birth of the child, together with the fact that an organism is immune to 
its own proteins, makes me believe that the foreign protein of the male 
brought in with the spermatozoan marks the starting point of the intoxi- 
cation. In this sense the morning sickness, the nausea, etc., occurring 
early in the pregnancy mark the beginning of the intoxication, but as 
immunity is usually established they are likely to pass away. When 
immunity is not established the severer signs of the later months of preg- 
nancy supervene. A woman who has once been pregnant is less likely to 
be a second time the victim of an intoxication, because the immunity 
developed in a first pregnancy protects her against the intoxication conse- 
quences of a second. Moreover, a woman married more than once may show 
intoxication with one and not with another man (because the foreign pro- 
tein is different in the two). Termination of the pregnancy (removal of 
the foreign protein as contained in the developing embryo) cuts short the 
intoxication. Many circumstances, moreover, serve to aggravate the 
nephritis encountered in pregnancy when it has once become established. 
Such are the " acidosis," for example, secondary to the starvation conse- 
quent upon the vomiting, the nausea, and the absurd dietary restrictions 
to which these patients are so often subjected, a state betrayed only too 
clearly by the high ammonia excretion and the presence of acetone, diacetic 
acid, etc., in the urine. 

I should further like to emphasize that not every nephritis observed in a 
pregnant woman is at once to be attributed to the pregnancy, as is so gen- 
erally done. Vascular disease and infections of the kidney are very com- 
monly overlooked. It has also been my experience that many patients 
are said to have a pregnancy intoxication resulting in the death of the fetus 
when as a matter of fact syphilis or some other condition first killed the fetus 
and the products of its decomposition then served to affect the kidney. 



NEPHRITIS 705 

Case XV. — (Dr. James J. Hogan, San Francisco, California.) Mrs. 
R., pregnant and practically at term, entered the hospital March 7, 
1911, at 5.30 p.m., complaining of continuous uterine pain. She had a 
general cedema. Signs and symptoms indicating that a nephritis had 
existed for at least some days past were evident, but no proper examina- 
tion of the urine had been made. The os on examination was found 
rigid. Because of the intense pain 0.015 gram morphin was given 
hypodermically at 9.00 p.m. She went to sleep but awoke at 11.00 in 
a severe convulsion. The patient was catheterized and 60 cc. of bloody 
urine of a syrupy consistency were obtained. On testing this for albumin 
it fairly set. Casts, cellular detritus, red blood cells, etc., were found 
microscopically. 600 cc. of an 0.85 per cent sodium chlorid solution 
were given by rectum and immediate emptying of the uterus was deemed 
necessary. This was done under ether anethesia and as the os was 
very rigid required a half hour. A second convulsion occurred on 
the operating table. Immediately after the operation another 500 
cc. of an 0.85 per cent sodium chlorid solution were given by rectum. 
Between this time (11.30 p.m., March 7) and 4.50 p.m., March 11, in 
other words, for practically four days, no urine could be obtained by 
catheter. During this time no convulsions occurred and the patient's 
mind remained clear. A continuous salt drip was used in the rectum 
and water and magnesium sulphate were given by mouth, but no evidence 
of a return of urinary function was obtainable. It was now decided to 
use a more concentrated sodium chlorid solution and alkali. The 
following mixture was therefore prepared: 

Sodium carbonate (Na 2 C0 3 - IOH2O) 20 grams 

Sodium chlorid 14 grams 

Water, enough to make - 1000 cc. 

This was injected into the rectum at body temperature by a con- 
tinuous drip method. In an hour and ten minutes 30 cc. of bloody 
urine were obtained, and an hour later 80 cc. more. From now on the 
urine fairly streamed out. The secretion continued and the albumin 
and casts entirely disappeared from the urine by the fourth day. The 
patient made an uninterrupted recovery. 

Case XVI. — (Dr. Lemuel P. Adams, Oakland, California.) Mrs. 
E., twenty-six years old and a primipara, began to feel below par, became 
pale, and developed a generalized cedema when pregnant seven and a 
half months. The secretion of urine was low, and this contained much 
albumin and various casts. Her condition gradually grew worse, so 
that it was deemed wise to put her to bed in the hospital. For ten 
days here, on a milk diet, and cared for in the approved ways, she 
showed no improvement, passing between 240 and 360 cc. of urine 
per twenty-four hours, filled with albumin, casts, and red and white 
blood corpuscles. As she now began to develop twitchings, was extremely 
cedematous and nearly blind, and as the onset of convulsions was feared, 
premature labor (at 8 months) was induced through gradual dilatation 
of the uterine os by means of water bags. "Complete suppression of 



706 



(EDEMA AND NEPHRITIS 



urine followed delivery. After this had lasted for thirty-one hours 
and no urine had come consequent upon hot packs, cupping, digitalis, 
etc., a slow injection of the following mixture into the rectum was begun: 



Urine began to come four hours after the injection was commenced 
and amounted to 1536 cc. in the first twenty-four hours. Two injec- 
tions daily of 500 cc. each of the above formula were continued for 
three days, together with water, milk, and cereals by mouth. On the 
second day 2176 cc. of urine were obtained, on the third 2140, on the 
fourth 2180, and on the fifth 1856. On the fifth day casts and blood 
cells had entirely disappeared from the urine and only the faintest trace 
of albumin remained. The oedema had diminished greatly, eyesight 
was returning, and the patient was actively interested in her surround- 
ings. On the following day the last of the albumin was gone and the 
patient went on to an uneventful recovery. 

Case XVII. —(Dr. Dudley Smith, Oakland, California.) Mrs. 
W., aged thirty, and seven months pregnant, presented herself for 
examination in May, 1911, with a history of nephritis and threatened 
eclampsia in her first pregnancy, ten years before. The second preg- 
nancy, three years before, had been uneventful. Urinary examination 
when the patient first presented herself was negative. On June 7, 
she began to show albumin in her urine and marked signs of general 
intoxication. (Edema of the face and feet developed. She was put to 
bed and placed on a milk diet, and saline cathartics were administered. 
Under this treatment she got no better. About the first of July, active 
administration of alkalies was begun in the form of 1 to 1| grams of 
sodium carbonate dissolved in a glass of plain water, or Vichy water, 
every two hours. Marked and positive improvement occurred in all 
her general symptoms and the oedema disappeared entirely. She was 
permitted to get out of bed again, but the alkali therapy was continued. 
On this regime she was carried to full term with no further general symp- 
toms of consequence. Her urinary output lay between 1800 and 2800 
cc. daily and some albumin and casts continued in the urine. On 
July 24 she complained of severe continuous uterine pain, and with 
this came a marked reduction in the urinary output, extreme nervous- 
ness, and severe headache with nausea and vomiting. On the morn- 
ing of July 25 the urinary secretion had stopped entirely. She was sent 
to the hospital at noon and the following formula was slowly injected 
into the rectum: 

Sodium carbonate (Na 2 C0 3 • 10H 2 O) 15 grams 

Sodium chlorid 14 grams 

Water, enough to make 1000 cc. 

At 3 p.m. the uterine pain, the headache, and the nausea had 
disappeared and the patient went to sleep. At 4 p.m. the rectal 



Sodium carbonate (Na 2 C0 3 • 10H 2 O) 

Sodium chlorid 

Water, enough to make 



,20 grams 
14 grams 
1000 cc. 



NEPHRITIS 



707 



infusion was given a second time and almost a liter was absorbed. At 
11 p.m., 258 cc. of urine were voided and the patient passed a good 
night, sleeping soundly. The following morning 500 cc. of urine, very 
high in albumin, casts, and blood, were passed. At three o'clock of this 
day, she again developed severe headache, nausea, and vomiting, and 
was unable to retain the rectal infusions, or anything by mouth. At 
10 p. m. all the symptoms had so increased in severity, that 300 cc. 
of the above solution were given intravenously. In fifteen minutes 
the patient volunteered the information that her headache and nausea 
were gone. She was comfortable until the next afternoon, when periodic 
uterine pains developed, and the headache and vomiting returned. The 
patient was taken to the operating room, and the cervix was dilated 
slowly by hand. Delivery of the living child was accomplished in an 
hour and a half. This was followed by another intravenous injection 
of 645 cc. of a solution containing 1\ grams sodium carbonate 
(Na 2 CCV 10H 2 O) and 14 grams sodium chlorid to the liter. In the 
following twenty-four hours 2200 cc. of urine were voided, and as the 
nausea, vomiting, etc., had disappeared it was an easy matter to main- 
tain such a urinary output by giving water and alkalies by mouth. 
Albumin and casts disappeared from the urine on the fourth day and the 
patient had an uneventful convalescence. 

Case XVIII.— (Dr. W. A. Clark, Oakland, California.) Mrs. 
C. H., aged thirty-five, and pregnant for the second time, presented 
herself for examination in March, 1911. She had menstruated slightly, 
and for the last time, January 22. A year previously she had given 
birth to a healthy child at term, though in the later months of her preg- 
nancy her limbs and face had swelled, she had much headache, and her 
eyes had troubled her. At the time of her first visit, and repeatedly 
afterward, physical examination and examination of the urine showed 
nothing abnormal. On August 11, she showed a well-marked gen- 
eralized cedema, and complained of headache, extreme restlessness, 
sleeplessness, dimness of vision, and constant nausea. Her urinary 
secretion had fallen to 500 cc. per twenty-four hours, was highly acid, 
and high in albumin and casts. She was immediately sent to the hospital 
and kept in bed on a diet rich in water, alkalies, vegetables, and milk. 
Epsom salts were administered by mouth, and 0.85 per cent sodium 
chlorid solution was repeatedly injected slowly into the rectum. On 
this regime all of her symptoms and signs, including the albumin and 
casts, disappeared, and the urinary output rose, so that 2200 to 2674 
cc. were voided every twenty-four hours. August 26 the patient felt 
so well that she insisted on getting out of bed and busying herself about 
her room. On the second day following this renewed activity, her 
headaches again showed themselves, and her nervousness and sleepless- 
ness returned. On August 29 her nausea and vomiting became severe, 
and hfer vision very dim. The cedema of the legs and face returned, and 
her urinary output fell slightly, to 1984 cc. When the heat test was 
applied to the urine, the whole became solid. This condition continued 



708 



(EDEMA AND NEPHRITIS 



until 11.30 p.m. of August 30, when the headache, nausea, vomiting, 
etc., were so severe that it was decided to give alkali and salt intra ven- 
ously. The following formula was given: 



In an hour the patient volunteered the information that her head- 
ache and nausea were better, and that she felt brighter. She slept 
well, and passed the next morning comfortably. Examination of the 
urine passed in the night and early morning showed a decided drop in 
the amount of albumin excreted. Even though the subjective symptoms 
of the patient continued well, the albumin content of the urine again 
rose so that on the morning of September 1 this was sufficient to make 
the contents of the test-tube again set in a solid mass when boiled. The 
amount of urine obtained continued good, being 1984 and 2048 cc. 
respectively, for the last two twenty-four-hour periods. It was deemed 
best to empty the uterus, and at 10 a.m. of September 1, dilatation 
of the uterine os by means of rubber bags was begun. Rh}i;hmic pains 
began two hours later and as these increased in number and severity, 
the patient's headache and nausea increased, and the urinary secretion 
fell. At 4 p.m. the patient vomited and developed a twitching of the 
face and arms. This continued at intervals until 11 p.m. when two 
liters of the alkali-salt mixture of the composition previously used in 
this case, were injected intravenously. Shortly after this, the sub- 
jective symptoms of the patient became better and she fell asleep, 
passing a fairly good night, and examination of the urine again showed 
a decided drop in the amount of albumin present. The general condi- 
tion of the patient continued good, and on the evening of September 
2, she was delivered under chloroform anesthesia of a 1750-gram, living, 
female child (left shoulder presentation with version). On the operat- 
ing table the patient received 1000 cc. of 0.85 per cent sodium chlorid 
solution under the skin, and for subsequent treatment the patient was 
given this same salt solution by rectum. Alkaline water (a gram of 
sodium carbonate in a glass of water every hour) was given by mouth. 
The urinary secretion on this regime never fell below 2200 cc. On 
September 4 the albumin in the urine had dwindled to a trace, and on 
the next day it disappeared entirely. Examination of the urine twice 
daily from this time on invariably showed an alkaline reaction to litmus 
paper and no albumin. The general oedema disappeared on the third 
day after delivery. On September 17 the patient was fully convalescent. 

Case XIX.— (Dr. N. A. Hamilton, Franklin, Ohio.) Mrs. C, 
twenty-seven years old, and a primipara in the seventh month, showed 
nothing abnormal on examination, September 8. On September 20 
some albumin was found in the urine, and on September 27 it was present 
in abundance. Her general condition was good. 

At 10 p.m., October 2, she was seized with sudden nausea and 
vomiting which continued through the night. At 3.30 a.m., October 



Sodium carbonate (Na 2 C0 3 • 10H 2 O) 

Sodium chlorid 

Water, enough to make 



10 grams 
14 grams 
1000 cc. 



NEPHRITIS 



709 



3, she had short lapses of consciousness. . Headache was severe; there 
was some oedema of the face and legs; the pulse was 100 and hard. 
Veratrum was given by hypodermic injection. At 8.30 a.m. her pulse 
had fallen to 52; her temperature was nornal. No urine had been 
passed through the night, but at this time she passed 30 cc. The patient 
was dizzy, still vomiting, had pain in her neck, and her sight was blurred. 
She was now given 800 cc. of a strong (hypertonic) sodium chlorid solu- 
tion (1.5 per cent) by rectum. This was all retained. At 11.30 a.m. 
90 cc. of dark-colored urine filled with casts and containing so much 
albumin that on boiling it fairly set was passed. Another 800 cc. of 
the sodium chlorid solution were now given and at 2 p.m. an unknown 
amount of urine was lost with a stool. Twenty minutes later a con- 
vulsion lasting a minute occurred, and this was repeated a half hour 
later. The patient was vomiting, and could not distinguish colors. 
There was a general twitching of the muscles. A general anesthetic 
was given at 3.30 and an attempt made to dilate the very rigid uterine 
os instrument ally. At 5.00 p.m. the membranes ruptured, and at the 
same time 30j3C of dark-brown urine were obtained by catheter. At 
6 p.m. the temperature of the patient was 100.2° F. by axilla. Another 
injection of 800 cc. of the strong saline solution was given by rectum 
at this time and repeated at 8 p.m., but neither was retained well. 
At 10 p.m. a little urine (estimated as 30 cc.) was passed with a stool. 
At midnight the patient's temperature was 100.2° F., she was dizzy, 
could not distinguish between men and women, and was unable to 
differentiate white from black. At this time she was given the following 
formula intravenously: 

Sodium carbonate (crystallized) 20 grams 

Sodium chlorid 28 grams 

Water, enough to make 2000 cc. 

The injection required an hour. While giving the injection the 
patient volunteered the information that her nausea had left her, and that 
her headache was disappearing. At 2.30 a.m., October 4, she passed 75 
cc. of dark-brown urine filled with casts and fairly solid with albumin 
on boiling. At 4 a.m. she passed another 75 cc. and at 6.45 a.m. 
95 cc. During these hours she slept at intervals. When she awakened 
her headache and nausea were gone, and she could distinguish between 
gross objects, and recognize colors. From now on and through the day 
she was plied with water by mouth and five injections of 400 cc. each 
of the above sodium carbonate-sodium chlorid mixture were given 
by rectum. These were well retained. Urine was voided about every 
three hours, and in increasing quantity. By midnight, that is to say 
in the first twenty-four hours after the intravenous injection, she had 
voided 572 cc. not counting two " large " voidings that were lost. The 
later portions of this urine were clearer in color and contained much 
less albumin than the specimens already described. 

In the night of October 5, the patient went into labor, and at 8 
a.m. forceps were introduced and she was delivered of a macerated fetus. 



710 



(EDEMA AND NEPHRITIS 



In spite of the exertions of labor she passed 320 cc. of urine between mid- 
night and the time of the delivery of the placenta. Through the night 
the alkali-salt enemas could not be retained, but through the day she 
took and retained four enemas of 400 cc. each. In this second period 
of twenty-four hours she passed 734 cc. of urine. After delivery, her 
temperature, which on the night before had risen to 103.6° F. (by mouth), 
fell to normal. 

In the twenty-four hours of October 6, she received and retained 
four enemas of 500 cc. each of the alkali-salt mixture, and drank freely 
of water (a glass every hour) . She passed in this period 1840 cc. of urine, 
not counting two voidings that were lost with the stools. The later 
portions of this urine contained only a little albumin. The patient 
was sleeping well, and relishing her toast, gruel, eggs, milk, and broth. 

In the next two days the alkali-salt enemas were reduced to two 
daily, one night and morning, and then stopped entirely. She was 
given a liberal diet, and water was insistently given by mouth. Lemonade 
and orangeade were urged. When the alkali was no longer given by 
rectum, sodium carbonate (0.5 gram) was given in a glass of water as 
often as the patient would take it both day and night, and she was asked 
to salt her food liberally. Her urinary output on this regime was as 
follows : 

October 7 3616 cc. October 14 2400+ cc. 

October 8 3264 cc. October 15 4096+ cc. 

October 9 3520 cc. October 16 3808 cc. 

October 10 2528 cc. October 17 3200 cc. 

October 11 2108 cc. October 18 1920 cc. 

October 12 2396 + cc. October 19 1915 cc. 

October 13 2432+ cc. 

The great rise in urinary output on October 15 followed an increase 
in the amount of alkali and salt given by mouth; the fall on October 
18 a reduction of this. 

The oedema had disappeared and the albumin dwindled to a trace 
by October 7. This trace persisted up to October 19. The patient 
developed a slight temperature (100.8° F.) on the fourth day after 
delivery, but following intrauterine douches with bichlorid of mercury 
and iodin this fell so that only a temperature of 99° or 99.2° was 
registered in the afternoons up to October 17. From October 16 she 
was given an unrestricted diet, and on October 17 she sat up for the 
first time. On October 24 she " is downstairs, voiding an abundance 
of urine and happy." Recovery was complete. 



Case XX— (Dr. E. A. Majors, Oakland, California.). Mrs. A. B., 
pregnant for the second time and at term was found in labor and delivered, 
of a healthy living child, in an entirely normal way at 1 a.m. No 
previous history was obtainable. Following labor she fell into a deep 
sleep and at 5 a.m. it was impossible to arouse her. As there was 
no evidence of urinary secretion, she was cathetenzed at 6 a.m. 



NEPHRITIS 



711 



No urine was obtained. At 7 a.m. she had two severe convulsions. 
Following this she lay in a deep stupor with rapid breathing. At 10 
she was again catheterized, but no urine was obtained. She now 
received by slow injection into the rectum the following: 



Sixty cc. of urine were obtained an hour after the beginning of 
the injection, and half an hour later another 130 cc. filled with albumin 
and casts. At the same time the patient began to clear mentally. 
Three hours after beginning the injection she would respond to ques- 
tions. From this time on she was plied with water by mouth. Later 
in the afternoon 500 cc. of the above formula were again given by rectum 
and this was repeated next day. In the first twenty-four hours 1525 
cc. of urine were obtained, and in the second 2240 cc. At the same 
time the albumin and casts diminished and on the third day the urine 
cleared entirely. Uneventful convalescence followed. 

Case XXI— (Dr. C. C. Fihe, Cincinnati, Ohio.) Mrs. E. J. H., 
aged twenty-six years, showed much albumin and many casts in her urine, 
and developed a generalized oedema in the seventh month of this, her 
first pregnancy. Her urinary output was scanty and highly colored, 
and she felt herself below par. Her physical activities were much 
restricted, and she was placed on an active alkali therapy. Vegetables 
and sweet fruits were urged upon her, sodium phosphate and citrate 
were frequently given, and at regular intervals sodium carbonate and 
sodium chlorid were administered in capsules followed by water. Her 
symptoms cleared markedly, and she was carried to term, voiding 700 
to 1500 cc. of urine daily. 

At midnight, February 1, she went into labor, and at 8.30 a.m. was 
delivered of a living child. She had passed no urine the day previously, 
and none was passed during these hours. A gradually increasing blurred 
vision in her right eye, of which the patient had complained, for several 
days past, had increased. She complained of headache. At 11 a.m. 
a convulsion lasting ten minutes occurred, and at 2.30 p.m. another last- 
ing twenty minutes. At both times chloroform was administered. 
She was catheterized and 30 cc. of dark brown urine filled with albumin 
were obtained. At 5 p. m. catheterization was dry. The pulse ranged be- 
tween 148 and 92. At this time 150 cc. of the following solution were 
given intravenously : 

Sodium carbonate (Na 2 C0 3 • 10H 2 O) 10 grams 

Sodium chlorid 14 grams 

Water, enough to make 1000 cc. 



Sodium carbonate (Na 2 C0 3 • 10H 2 O) 

Sodium chlorid 

Water, enough to make 



15 grams 
14 grams 
1000 cc. 



'A severe convulsion occurred while the intravenous injection was 
being made, and so this had to be discontinued. 0.015 gram morphin 



712 



(EDEMA AND NEPHRITIS 



was given h5 r podermically, and another 250 cc. of the solution were 
injected into the rectum. At 8.15 p.m. 1200 cc. of urine were obtained 
by catheter from the bladder. At 8.45, 1200 cc. of the above solu- 
tion were given intravenously. An unmeasured amount of urine was 
passed with a stool at 10.30. At 11, 1022 cc; at 12.30, 96 cc; at 2.40, - 
16 cc; at 6.40, 512 cc. were passed voluntarily. The pulse gradually 
fell during these hours to 76. Sodium phosphate, sodium carbonate, 
and sodium chlorid were given in small doses at regular intervals by 
mouth, and after the first signs of a freer urinary output, water and milk 
were urged at hourly intervals. In ,the first twentj^-four hours after 
the intravenous use of the alkaline hypertonic salt solution, 4814 cc. 
of urine were passed, not counting -two voidings that were lost. The 
patient's uneventful subsequent history is summarized below. Five 
grams each, per twenty-four hours, of sodium chlorid and sodium 
carbonate were given in divided doses in capsules followed by water, 
at regular intervals day and night. In addition, 15 grams of disodium ' 
phosphate were given once or twice daily, and for the patient's anemia, 
0.5 cc tincture of iron chlorid three times daily was prescribed. 



Date. 


Temperature. 


Pulse. 


Urine in 
24 hours. 


Albumin in 
grams per 

liter 
(Esbach). 


Remarks. 


Feb. 2-3 


98 


0° to 98 


6° 


78 to 80 


4128 + 


1.0 


Milk diet. 


Feb. 3-4 


98 


2° to 98 


6° 


68 to 78 


5578 


0.5 


Milk diet. 


Feb. 4-5 


98 


2° to 98 


6° 


64 to 74 


4127 


0.5 + 


Light mixed diet. 


Feb. 5-6 


98 


2° to 99 


2° 


72 to 86 


5382 


0.5 


Light mixed diet. 


Feb. 6-7 


99 


0° to 100 


2° 


74 to 86 


4288 


0.5- 


Light mixed diet. 


Feb. 7-8 


98 


6° to 99 


6° 


74 to 80 


3904 


0.25 


Light mixed diet. 


Feb. 8-9 


98 


0° to 98 


6° 


68 to 75 


5272 


Trace 


Light mixed diet. 


Feb. 9-10 


98 


6° to 99 


0° 


68 to 72 


4032 


Trace 


Light mixed diet. 


Feb. 10-11 


99 


8° to 98 


0° 


70 to 72 


2200 + 


Trace? 


Light mixed diet. 


Thereafter until 














No dietary 


March 10 




Normal 




Normal 


1700 to 2700 


No albumin 


restrictions. 



Case XXII.— (Dr. W. A. Clark, Oakland, California.) The his- 
tory of Mrs. H., aged twenty-three years, as well as it could be obtained, 
brought out the fact that she had been markedly cedematous and had 
had headaches and a scant}' urinary output for several weeks past. 
At 5 p.m. of November 14, 1911, she gave birth to her first and living 
child. At 9 she had a convulsion that lasted fifteen minutes, and four 
more occurred in the night. She became unconscious. At 7 the next 
morning she was removed to the hospital. A severe convulsion occurred 
in the ambulance, and five more before 7.30 that evening. The patient 
vomited several times, the pulse ranged between 140 and 160, the respira- 
tion was 36 and the unconsciousness continued. In these twenty- 
seven and one-half hours she was effectively sweated several times, two 
magnesium sulphate and glycerin enemas were given, and two liters 
of 0.85 per cent sodium chlorid solution were given subcutaneously; 
210 cc of bloody urine filled with albumin were obtained by catheter 
during these hours. 



NEPHEITIS 



713 



At this time two liters of the following solution were given 
intravenously : 

Sodium carbonate (Na 2 C0 3 • 10H 2 O) 10 grams 

Sodium chlorid 14 grams 

Water, enough to make 1000 cc 

An hour later on involuntary urination occurred, of which only 
320 cc. were caught; at 10.30 occurred a second, and at 11.30 a third. 
At 2.15 in the night the patient was rational for a few minutes, and at 
8.30 a.m. she awakened completely. Through the day she was given 
1000 cc. of the above formula by slow drip into the rectum, and water 
by mouth ad libitum. The total urinary output in this twenty-four- 
hour period was 3986 cc, and except for the first specimens which were 
bloody, the urine was fairly clear, intensely acid, and filled with albumin 
and casts of all kinds. The pulse which at the time of the intravenous 
injection was 140, rose to 150 after the injection, to fall gradually to 102 
by the next morning. 

In the next twenty-four-hour period the injection by rectum of the 
alkaline hypertonic sodium chlorid solution was continued, about 300 
cc. being injected and retained every six hours. Alkaline water by 
mouth was freely urged day and night. At 8 a.m. of November 17 the 
urine was neutral for the first time, and of a clear amber color. The 
total urinary output for this twenty-four-hour period was 3300 cc, 
with considerable albumin still present. 

The history of the next five days is indicated in the following 
summary : 



Date. 


Tempera- 
ture. 


Pulse. 


Respi- 
ration. 


Urine 
in 24 


Character. 


Remarka. 








hours. 






Nov. 18 


99.4°-97.8° 


104-84 


24-20 


3840 + 


Dark amber 
to clear. 
Neutral, 
no albu- 
min. 


600 cc. alkaline hypertonic 
salt solution by rectum. 
Glass of alkaline water 
every half hour, day and 
night, by mouth. 


Nov. 19 


99.8°-97.8° 


108-92 


20 


5216 


Clear, neu- 
tral, no t 
albumin. 


(Edema of limbs subsiding. 
Solid food allowed. Al- 
kali by mouth only. 


Nov. 20 


99.8°-97.4° 


108-88 


20 


3552 + 


Clear, neu- 
tral, no 
albumin. 


(Edema of limbs subsiding. 
Solid food allowed. Al- 
kali by mouth only. 


Nov. 21 


99.8°-97.8° 


112-88 


20 


3840 


Clear, neu- 
tral, no 
albumin. 


(Edema noticeable in 
flanks only. Gone from 
rest of body. Alkali by 
mouth only. On light 
general diet. 


Nov. 22 


98.4°-98.0° 


100-80 


20 


3600 


Clear, neu- 
tral, no 
albumin. 


(Edema entirely gone. 



From this time on until her discharge from the hospital, December 
5, her history was uneventful. Her diet was unrestricted except that 
alkali was added to her drinking water, given both day and night, and 
she was urged to salt her food. 



714 



(EDEMA AND NEPHRITIS 



Case XXIII. — (Dr. N. A. Hamilton, Franklin, Ohio.) During 
the last week of her pregnancy, Mrs. M., aged twenty-nine years, had 
oedema of the legs, and suffered from impairment of vision to the extent 
of not being able to recognize her friends on the street. Her urine 
during this period was not brought to her physician for examination, 
though previous examinations had been negative. At term, on March 
24, she went into labor, and was delivered normally of a living child by 
Dr. S. S. Stahl. The delivery occurred rapidly. The patient made 
normal progress until the fourth day (March 27), when she developed 
a temperature of 102° F., with a pulse of 110. This was attributed 
to an infection of the parturient canal. At the same time she became 
markedly nervous, complained of headache, and had great roaring in the 
ears. The urine became very scanty, and heavily charged with albu- 
min and casts. This condition continued until March 31. On this 
day the pain in the head became very severe, nausea and vomiting 
occurred, and a marked numbness of the right arm and leg developed. 
The patient was pale and generally oedematous. There was a twitch- 
ing of the muscles in various parts of the body. At noon on this day an 
active administration of sodium carbonate and sodium chlorid by mouth 
(0.33 gram each, every hour, with half glass of water) was started, and 
on the succeeding day this was given in the following form by rectum: 

Sodium carbonate (Na 2 C0 3 - 10H 2 O) 10 grams 

Sodium chlorid 14 grams 

Distilled water, enough to make 1000 cc. 

f~In the twenty-four hours during which the sodium chlorid and 
sodium carbonate were given by mouth, the patient's condition improved 
only slightly. On the following day, when administration by rectum 
was commenced, . a rapid clearing began. The patient's history is 
summarized in the following table. 



24-hour 


High- 


Highest 










period 


est 


temper- 


Urine. 


Medication. 




Remarks. 


ending 


pulse. 


ature. 










April 1 


110 


102.0° 


720 


Salt and alkali 
mouth. 


by 


Signs and symptoms as above. 
General twitching. Much 
albumin. 


April 2 


115 


102.2° 


3420 


Salt and alkali 
rectum. 


by 


General symptoms better. 
Albumin less. 


April 3 


100 


101.0° 


2730 


Salt and alkali 
rectum. 


by 


Patient comfortable; no head- 
ache, nausea or vomiting. 
CEdema less. Albumin very 
much less in amount. 


April 4 


80 


101.0° 


3060 


Rectal administration 


Same. QSdema lessening. 










stopped. Alkali 


and 


Albumin in traces only. 










salt by mouth only. 




April 5 


78 


101.3° 


2700 


Salt and alkali 
mouth only. 


by 


Traces of albumin only. 


April 6 


84 


101. 1° 


1680 


Salt and alkali 
mouth only. 


by 


No albumin or casts. 


April 7 


84 


100.4° 


1110 


Salt and alkali 
mouth only. 


by 


No albumin or casts. 


April 8 


80 


100.4° 


1530 


Salt and alkali 
mouth only. 


by 


No albumin or casts. 


April 9 


78 


100. 1° 


1500 


Salt and alkali 
mouth only. 


by 


All oedema gone; patient feels 
entirely well. No albumin 
or casts. 



NEPHRITIS 



715 



The temperature continued a few days longer, but otherwise the 
patient went on to an uninterrupted recovery. 

Case XXIV. — (Dr. Carl E. Curdts, Oakland, California.) Mrs. 
A. B. J., aged twenty-three years, entered the hospital, practically 
at term, in the early morning of July 14, 1912. She had always been 
well, and up to the eighth month of this, her first pregnancy had noted 
nothing abnormal. At this time her feet began to swell and her face 
became puffy, and some albumin and casts were found in her urine. 
In the ten days before entering the hospital she had been on a milk diet, 
and largely in bed. Nevertheless, she had grown progressively worse, 
her oedema becoming general and marked, and her urinary secretion 
dropping to " less than a pint measure " a day. Headache in the last 
two days had been constant. Her eyesight had been failing for a week 
past, so that on admission she could only distinguish light from darkness 
with her left eye, and with her right she could only recognize gross 
objects at a distance. In the last day before coming to the hospital, 
and during the morning at the hospital she complained of " twitching 
and nervousness." 

At noon of her first day in the hospital she passed 90 cc. of urine — 
the first since the night before, according to her statement. This urine 
was deep amber, rather syrupy, and acid to paranitrophenol. On 
boiling with acetic acid the urine set into a solid jelly. An Esbach 
determination, using citric-picric acid as the reagent, showed 14 grams 
of albumin to the liter. The urine was filled with casts, mainly hyaline. 
The patient's pulse was 102, her temperature normal. 

While immediate delivery by vaginal Csesarean section had been 
recommended, it was felt, for reasons to be discussed later, that no such 
immediate haste was necessary. She was, in consequence, given the 
following formula by slow drip into the rectum: 

Sodium carbonate (Na 2 C0 3 • 10H 2 O) 10 grams 

Sodium chlorid ^ . 14 grams 

Distilled water, enough to make 1000 cc. 

She took the drip well, and in the course of the afternoon absorbed 
and retained 720 cc. At 3.30 p.m. she voided 378 cc. of urine; at 6.45, 
300 cc; at 8.55, 90 cc; and at midnight 315 cc. The patient's pulse 
gradually fell to 82 by 5.30, and remained here. At the same time she 
volunteered that her headache was much improved, and that she could 
see more clearly. In the night of July 15 she was given 420 cc. more 
of the solution by rectum. At 2.30 a.m. she voided 150 cc. of urine; 
at 4, 60 cc; at 8.30, 120 cc; at 10.20/60 cc, and at noon, 63 cc 
The total urine for these first twenty-four hours in which the alkaline 
hypertonic sodium chlorid solution was given was, therefore, 1536 
cc. In spite of the disturbance incident to giving her the solution, 
the patient insisted this morning that her headache was almost gone, 
that her eyesight had greatly improved, and that she felt more comfort- 
able than for several days past. The urine had gradually decreased 
in acidity, so that the second specimen obtained after starting the drip 



716 



(EDEMA AND NEPHEITIS 



was neutral to litmus. The Esbach determination showed a drop to 
7.5 and 6.5 grams of albumin to the liter. The later specimens of urine 
clearly indicated that a higher salt concentration was prevailing in the 
body because the albumin on boiling with a drop of acetic acid no longer 
jellied, but was precipitated in flocculent masses. 

In the early afternoon of July 15 the patient experienced some uterine 
pains, which gradually became more severe. Because of them the rectal 
injections were stopped. The patient was given as a substitute 8 grams 
of sodium citrate daily, b} T mouth in several small doses. At 7.30 p.m. the 
pains became very severe and frequent, and at 11.30 she delivered herself 
of a healthy, living, male child. Ether was administered, and forceps 
were used to accelerate labor after the head appeared at the vulva. 
In the hours while the pains were on, the patient's headache increased, 
but otherwise she continued to feel well. The pulse rose from 82. when 
the first labor pains were felt, to 102 between the pains, when delivery 
was in actual progress. Up to the time of deliverv she passed 270 cc. 
of urine, and at 10.30 the next morning 340 cc. were obtained by 
catheter. Both these specimens were dark amber, intensely acid to 
methyl red, and barety alkaline to paranitrophenol, gave a heavy curdy 
precipitate on boiling with acetic acid, and showed 15 grams of albumin 
to the liter (Esbach). Every field of a centrifuged specimen contained 
dozens of hyaline and finely granular casts. At this time her headache 
was slight, her eyesight more blurred than before labor, her temperature 
normal, and her pulse 88. 

At noon of this day, July 16, she was again started on the alkaline 
hypertonic sodium chlorid solution, and in the course of the afternoon 
absorbed 570 cc. At 4.15 she was catheterized and 690 cc. of urine 
were found, and at 11 p.m. another 780 cc. were obtained. The first 
of these specimens was paler than previous specimens, was still decidedly 
acid to litmus and methyl red, and contained 5 grams of albumin to the 
liter. Many granular and lwaline casts and red and white blood cor- 
puscles could be found in the sedimented urine. The second specimen 
was alkaline to methyl red and neutral to litmus and the Esbach deter- 
mination showed 2.25 grams of albumin to the liter. Only isolated 
casts could be found in the centrifuged specimen. The patient was 
now given 2 grams of sodium citrate by mouth every four hours, and 
milk and lime water every two hours. Through the night and up to 
noon of July 17 she passed 1770 cc, making a total for this twenty- 
four-hour period of 3210 cc. This night and morning urine was clear, 
neutral to litmus, alkaline to methyl red, showed a few granular and 
hyaline casts, and contained 1.75 grams albumin to the liter. The 
patient slept fairly well, said her headache was almost gone, and that 
she could again recognize the details of her surroundings. At noon 
she had no headache, could read the smaller letters of a newspaper, 
and showed a decided decrease in her general cedema. 

She was now given an unrestricted diet, to which she was urged to 
add plenty of table salt. Vichy water was urged upon her, to which 
several grams of sodium citrate were added. To the milk which she 



NEPHRITIS 



717 



consumed lime water was added. Her history is summarized in the 
following table: 



For 




Grams 




24-hour 
period 
ending 


Total 
urine. 


albumin 
per liter 
(Esbach). 


Remarks. 


at noon. 






July 18 


3280 


2.0 


XJnrestricted diotj Vichy waiter, milk with lime 
w^Sit>Br £nid 8 ^rdiins of sodium citrate per 24 hours. 
Some casts and white blood cells. 


July 19 


2520 + 


2.0 


Unrestricted diet, Vichy water, milk with lime 
water and 8 grams of sodium citrate per 24 hours. 
No general oedema visible. Eyes slightly puffy. 
Good appetite. Feels well. 


Tulv 20 


2366 + 


2.5 


Unrestricted diet, "Vichy water, milk with lime 
water and 8 grams of sodium citrate per 24 hours. 




C 11 1 S- 1X1 1 H £t 1 6 Q 




All signs of oedema gone. Only occasional cast m 




with, loctiisi 


men. only. 


centrifuged specimen. Some red and white blood 
corpuscles. Urine neutral. The albumin does not 
precipitate easily on boiling. 


July 21 


3000 + 


1.7 


No casts. Diet, Vichy water, etc., as before. Sodium 






citrate stopped and 0.7 gram of calcium chlorid 
every two hours day and night substituted for it. 
Urine faintly alkaline. Albumin comes down 
readily on boiling with acetic acid. Pulse 78; 
temperature normal. 


July 22 


2300 + 


1.0 


No casts. Diet, Vichy water, etc., as yesterday. 


July 23 


2250 + 


Trace 


No casts. 


July 24 


1980 + 


Trace 


No casts. Calcium discontinued. 


July 25 


2400 + 





Urine negative. 


July 26 


2136 + 





Urine negative. 


July 29 


2346 





Urine negative. Left hospital. 



At the present writing this patient is entirely well. 



§5 

We move from the protracted case of nephritis which is the 
result of a lasting intoxication of some kind by imperceptible 
steps over into the chronic nephritides. But as soon as we 
discuss the chronic nephritides we find that we have to distin- 
guish between those which represent a mere continuation of what 
was once a more acute process (the chronic parenchymatous 
nephritides, the secondarily contracted kidneys) and those which 
are chronic from the start, as in the type generally known as 
chronic interstitial nephritis (primarily contracted kidney) 
associated with changes in the vascular system. Very evidently, 
if our views are accepted, the nephritis which continues because 
of a protracted intoxication needs to be treated with alkali, 
salt and water in an equally protracted way. It has seemed 
to me that such a procedure yields good, and at times unexpect- 



718 



(EDEMA AND NEPHRITIS 



edly good, results, but I refrain from a detailed recital of 
such cases, for it is impossible, except as one works these 
things out for himself, to meet adequately the eternal argument 
that what has happened in such cases would have happened 
anyway. 

There is at hand, as a matter of fact, no dearth of the most 
objective sort of clinical evidence indicating the great 
value of alkali administration in such nephritides. F. T. Fke- 
richs 1 emphasized it in 1851 and the older generation of physi- 
cians bore him out in this. 2 A particularly careful clinical study 
of the effect of alkali on the signs and symptoms of nephritis 
was made more recently by Rudolf von Hoesslin. 3 He con- 
cludes that it is of great help in many cases, but fails in others, 
a view largely concurred in by such later studies as those of 
Glaesgen, 4 Ernst Romberg, 5 Fraenkel, 6 F. Conzen 7 and 

M. W. SCHELTEMA. 8 

The use of alkali by many of these authors was purely 
empirical, and even the more recent studies do little to interpret 
the positive or negative findings beyond asking whether a 
relationship exists between the " degree of acidity " of the urine 
and the intensity of the albuminuria, the number of casts, 
the urinary output and the general symptoms of the patient. 
It would take us too far afield to give our own interpretation of 
the findings of each of the authors, but if in reviewing their con- 
tributions there is kept in mind what has been written in these 
pages apparent contradictions will quickly pass. As might be 
expected, the best results are always recorded when nephritides 
essentially toxic and evanescent in type are treated, while a 
persistence of casts, albumin, etc., is most definite when vascular 
and irremedial heart disease lie behind the urinary findings. 
In the former instance the " acidity " of the urine is an index 

1 F. T. Frerichs: Die Brightsche Nierenkrankheit, Braunschweig (1851). 

2 See, for example, the standard texts of Senator, von Leube, Rosen- 
stein, Osler, and Dieulafoy. 

3 Rudolf von Hoesslin: Munch, med. Wochenschr., 56, 1673 (1909); 
Deut. Arch. f. klin. Med., 105, 147 (1912). 

4 Glaesgen: Munch, med. Wochenschr., 58, 1125 (1911). 

5 Ernst Romberg: Deut. med. Wochenschr., 38, 1073 (1912). 

6 Fraenkel: Deut. med. Wochenschr. 38 (1912). 

7 F. Conzen: Deut. Arch. f. klin. Med., 108, 353 (1912). 

8 M. W. Scheltema: Toedienung van Alkalien bij Albuminuric, Delft 
(1914). 



NEPHRITIS 



719 



of what is happening in the whole kidney and a reduction in 
it is certain to be paralleled by improvement in urinary findings. 
When only pieces of the kidney are involved in consequence 
of blood vessel disease or localized infections, then the mixed 
urine coming from diseased and well kidney substance together 
may easily be neutral or even alkaline, and yet no impression 
be made upon the albumin output, etc. And since the so-called 
consequences of kidney disease are usually nothing of the sort 
they may, of course, appear with any kind of kidney findings. 

Especially is it difficult to meet the argument that whatever 
improvement is noted in a nephritic would have occurred any- 
way when we deal with the chronic interstitial type associated 
with vascular disease. One can from the start foresee that 
such offers the least possible chance of being markedly benefited 
by an alkali-salt-water therapy, and in its final stages none 
at all. I have emphasized this repeatedly, and were it not for - 
the fact that it is upon this very type of case that some of my 
critics have based their arguments, it would scarcely be necessary 
to. refer again to some self-evident facts. How much and what 
can we do for such cases? 

The 'primary change in chronic interstitial nephritis associated 
with vascular disease is not nephritis, but vascular disease. Every 
experimental fact and all physiological reasoning bears this out. 1 
In consequence of the vascular disease one piece after another of 
the kidney suffers destruction. And as this blood vessel disease 
cannot be and is not materially influenced by the injection of alkali, 
salt, and water, so also can this therapeutic procedure be of little 
or no use in this type of disease. The only cases in which it can 
be of service are those in which the blood vessel disease is in itself 
not wholly responsible for the observed changes, but where other 
temporarily active factors have been or are also responsible in bring- 
ing about our clinical picture. 

An illustration of this is offered in Case VIII, outlined above. 
Here to the picture of an established chronic interstitial nephritis 
associated with vascular disease, was added an intoxication 
with an anesthetic. The exacerbation is represented by the 
effects of the anesthetic upon the kidney, which effects are added 
to those already produced in this organ by the irremovable blood 
vessel disease. Cold, hard muscular work, an infection, or an 

1 See page 614. 



720 



(EDEMA AND NEPHRITIS 



alcoholic spree might have done what the ether did. And the 
alkali, salt, and water would have relieved the consequences of 
such added factors equally well; but blood vessel changes that 
permanently interfere with the blood supply to a portion or all 
of an organ, especially when we deal with end-arteries, are not 
relievable by any such schemes. 

If this simple argument is borne in mind it will help to a better 
understanding of what may be, and what cannot be expected 
from the use of alkali, salt, and water in the chronic types of 
nephritis. 

Incidentally, we can also see what may be accomplished 
for the oedema, whether involving an individual organ or the 
whole body, in any case of heart disease. The final picture of a 
chronic interstitial nephritis is half the time not that of a pure 
nephritis, but one of this plus a failing heart. Only too often 
is the last insult administered to a remaining nubbin of kidney 
that for years, maybe, has served to keep a patient alive, by the 
cardiac muscle giving way (with a resulting generalized lack 
of oxygen, abnormal acid production and accumulation in all 
the tissues of the body, and so an oedema). When a heart, 
from any cause whatsoever, drops below the lowest level of an 
efficiency necessary to maintain a proper circulation, and has no 
remnants of recuperative powers left in it, alkali and salt can- 
not supply them. 1 

1 This is the type of case chosen by Joseph L. Miller (Amer. Jour. 
Med. Sci., 144, 8 (1912), Jour, Amer. Med. Assoc., 58, 1972 (1912)), upon 
which to test out the value of a salt-alkali therapy. According to his own 
statement, the majority of his cases were nephritides with permanently 
decompensated hearts. Naturally, alkali and salt could not produce a 
diuresis where the mechanism for water secretion was about -gone. Only 
heart tonics such as caffein and its derivatives, drugs, in other words, which 
through their action on the heart and respiration assured a temporarily 
better oxygen supply to the kidney and body tissues general^, gave a tem- 
porary '" diuresis." It was not necessary to be a believer in any of the 
colloid notions of water absorption to foresee all this, for, as we have 
known since 1860, an inadequate circulation will not allow even a normal 
kidney to secrete urine. 

More recently L. H. Xewbttrgh (Boston Medical and Surgical Journal, 
169, 40 (1913)), also concludes that the administration of alkali and salt is 
valueless or does actual harm in patients suffering from heart disease with 
broken compensation. To get at the real value of Xewburgh's evidence 
one must center attention not on the apparently convincing argument 
presented in his main text, but upon the protocols attached thereto. While 
Newbtjrgh claims to have kept his patients on a fixed dietary and. medical 



NEPHRITIS 



721 



§6 

Cases XXV and XXVI will illustrate the application of an 
alkali and salt therapy to clinical conditions which are, in general, 
regarded as consequences of an intercurrent " nephritis." To 
us they seem rather to illustrate the essential sameness that 
exists between that which in the kidney is called nephritis and 
that which in other organs goes by such special pathological 
or clinical names as cloudy swelling, stupor, coma, etc.; and 
as we found alkali and. salts of service in the former, it will not 
surprise us to find them of service in the latter also. 1 

Case XXV. — (Drs. Charles G. Pieck and E. M. Baehr, Cincinnati, 
Ohio.) The patient, E. E., aged six years, had scarlet fever on May 
19, 1912. The attack was characterized by an intense eruption, but 
relatively little fever, and no evident throat complications. He was 
up and around in less than a week. Twelve days later his mother called 
his physician because the boy had begun to complain of pain and 
distress in the throat. There was found an enlargement of the cervical 
glands, but nothing in the mouth or pharynx. The child grew worse 
during the week, becoming dull and listless, with no desire to eat, and 
sleepy and feverish. The boy's mother stated she knew he had not 
been passing a normal quantity of urine during this period. 

This condition persisted for two weeks, the child growing more and 
more listless until he was in a 'continuous state of lethargy. He was 
asleep most of the time and had to be aroused to eat. Only upon becom- 
ing aware that his feet had become swollen did the mother call the phy- 
sician a second time. At the time of his visit he found the child in a deep 

regime and then tested out the value of alkali and salt administration by 
adding this or taking it away, he actually did not do so. His patients received 
daily, in addition to a standard diet, digitalis and half an ounce (15 grams) 
of magnesium sulphate. On his test days he drops the digitalis and mag- 
nesium sulphate and substitutes a few grams of sodium bicarbonate. Of 
course, the urinary output had to fall and the oedema to increase, for what 
Newburgh did was to substitute for the large dose of that most powerful 
protein dehydrant, magnesium sulphate, a small one of the weakly acting 
sodium salt, while removing entirely the cardiac stimulant which alone 
was whipping up the heart to a point where enough oxygen was getting 
into the kidney to allow it to secrete any free water that might be brought 
it. His clinical results, aside from being fraught with experimental errors 
which vitiate his conclusions, could all be foretold. 

1 In connection with the idea that coma is an oedema of the brain occasioned 
by an accumulation of acid in it, it is an interesting fact that one of the 
harshest opponents of such a conception, namely, F. Marohand, has himself 
reported (Munch. Med. Wochenschr., No. 4 (1912)) the case of a patient 
comatose from poisoning with sulphuric acid who roused almost immediately 
after sodium carbonate was injected intravenously. 



722 



(EDEMA AND NEPHRITIS 



stupor with marked swelling of the face and feet. Slight convulsive 
manifestations were apparent. 

On the morning of June 25, almost one month, therefore, after the 
onset of the condition, the child was given an intravenous injection of 
two liters of the following solution : 

Sodium carbonate (Na 2 C0 3 - 10H 2 O) 10 grams 

Sodium chlorid 14 grams 

Distilled water, enough to make 1000 cc. 

No anesthetic was necessary, for the child was comatose. The veins 
were not collapsed and the injection was given more rapidly than usual, 
requiring but fifteen minutes. The child's mental condition cleared 
quickly, so that three hours after the injection he was able to recognize 
his surroundings and take water when asked to do so. In the twenty- 
four hours following the injection he was made to drink two liters of 
pure water. His improvement continued steadily. In three days the 
oedema had completely subsided, and the urine was flowing freely. 

Samples of the urine obtained before the administration of the alkaline 
hypertonic salt solution were intensely acid and held albumin and casts 
in abundance. The urine obtained on the morning before the injection 
was begun showed casts as well as blood cells. Urine obtained a few 
hours after the treatment was alkaline and still contained albumin, 
but the casts had apparently disappeared. The mother stated that 
the child passed his urine on the morning following the injection after 
getting out of bed and securing the chamber himself. 

The patient was kept in bed for four weeks, and the recovery was 
rapid and uninterrupted. The urine remained alkaline to metlryl 
red during this entire period. Albumin persisted in every sample 
examined, but no casts could be found. The quantity of albumin 
was always less than 1 gram as measured by the Esbach method. At 
the present writing (October 22) the boy is entirely well generally, but 
still has a small amount of albumin in his urine. - 

Case XXVI.— (Drs. G. M. Allen and E. M. Baehr, Cincinnati, 
Ohio.) The patient, W. S., was a boy aged seven years, who had never 
before been ill. On December 10, 1911, his mother observed that he 
was ailing, tired, and listless. He complained of some distress in his 
neck below the left ear, where there could be felt an enlargement of the 
cervical glands. A low-grade fever was present at this time. His throat 
and ears were examined but nothing unusual was discovered. This 
state of affairs continued until December 27, when his temperature 
rose to 103° F., and albumin and casts appeared in abundance in the 
urine. 

The following is a brief synopsis of the development and course of the 
case: 

From December 27 to January 3, 1912: The temperature ran an 
irregular course varying in intensity from 99° to 104° F. The average 
quantity of urine passed in twenty-four hours was 416 cc. Albumin 



NEPHRITIS 



723 



and casts persisted. During this period he was given daily per rectum 
an average of 500 cc. of the following solution: 



To January 10: The fever persisted, but was lower than during 
the previous week, fluctuating between 99° and 102° F. He passed 
an average of 640 cc. of urine daily. Albumin was constantly present, 
but was less in amount than before. 

On January 10 there was a slight transitory delirium; there was also 
observed a thin watery discharge from the left ear. The administration 
of the alkaline hypertonic salt solution was continued as before. 

To January 13: The temperature subsided gradually, reaching 
normal on January 12. The serous discharge from the ear continued. 
There was a leukocytosis of 34,000. On January 13, Dr. C. R. Holmes 
lanced the drums, but no pus was found. 

To January 17: The temperature remained normal on January 12, 
13, and 14, and the urine free of albumin. The patient voided about 
400 cc. daily. At this time a slight oedema of the face was seen, most 
pronounced under the eyes. His mental condition was quite good; on 
the morning of January 16 his mother read to him from his books, while 
he commented upon the pictures. That night without warning he 
developed a generalized convulsion which lasted two hours. The left 
side, apparently, was the worse involved. 

Dr. Holmes opened the left mastoid bone that night, the child 
having been given chloroform as an anesthetic. No pus was found. 
A second convulsion, lighter than the first, occurred later in the night. 

On the morning of January 17 the temperature was 103° F. The 
child was in a stupor from which he could not be aroused except with 
difficulty. There were continued spasmodic twitchings of the left arm 
and hand, and it was noticed that he did not move these parts as he 
turned in bed. The left leg also was not moved as freely as the right. 
Urine was voided involuntarily. Albumin was present in considerable 
quantities. 

At the request of Dr. Allen and Dr. Holt an intravenous injection 
was given by Dr, Baehr. One liter of the following solution was intro- 
duced into the superficial veins of the elbow. 

Sodium carbonate (Na 2 C0 3 • 10H 2 O) 10 grams 

Sodium chlorid 14 grams 

Distilled water, enough to make 1000 cc. 

On account of the collapsed condition of the veins as well as the 
slight oedema of the tissues, the veins could be found only by dissec- 
tion. No anesthetic was required. 

During the ensuing night the patient was given 1600 cc. of water by 
mouth. In the course of the next twenty-four hours there were passed 
1680 cc. of urine. Except in the earliest specimens there was no albumin 



Sodium carbonate (Na 2 C0 3 • 10H 2 O) 

Sodium chlorid 

Distilled water, enough to make. . . . 



10 grams 
14 grams 
1000 cc. 



724 



(EDEMA AND NEPHRITIS 



present even in traces. A blood examination made the morning after 
the injection showed a leukocytosis of 12,000. 

To January 21: The child rallied a bit in the course of the next 
twenty-four hours, the pulse rate and vascular tone remained quite 
satisfactory, and the mental condition cleared a little. It could be 
discerned definitely at this time that there was a complete left-sided 
hemiplegia, the arm and the hand being more severely involved than the 
leg. 

There was no fever, and the urine, for the most part, passed involunta- 
rily, was of satisfactory 7 quantity, and always free of albumin. On 
January 19 and 20 he became fretful and irritable, the oedema of the 
face became more intense, and a suspicion was aroused that his vision 
had become impaired. On January 21 his general condition was bad; 
the pulse, which had been of excellent quality during the entire illness, 
now became very weak and rapid, and he slowly sank into a stupor 
which was practically a coma. His pupils responded feebly if at all to 
light stimulation, and Dr. Holmes believed he was able to discern a 
congestion of the retinal vessels, although no extravasation or oedema of 
the discs was found. 

After consultation a second intravenous injection of the alkaline 
solution was administered, this time in the right external jugular vein, 
as no other veins in the extremities could be located. Two liters were 
given. Chloroform was used as an anesthetic, chiefly to keep the child 
quiet during the operation. The coma seemed deep enough to allow 
of a much more severe manipulation. The entire time consumed was 
thirty minutes. 

To January 30: In the first twenty-four hours he passed copious 
quantities of urine involuntarily. Water was given him to drink in 
large quantities, and milk alone was used for nourishment. Xeither 
albumin nor casts were found at any time during this period. He was 
restless during the nights. His mental condition cleared rapidly. Three 
days after the injection a test of his vision was made. He was able to 
recognize his parents and the physicians about him. 

Convalescence was slow though uninterrupted. Albumin never 
reappeared in the urine except upon one occasion when there was found 
a little circumscribed infection at the site of the first wound in the tissues 
of the elbow. As soon as proper drainage had been established the 
the albumin disappeared. 

The child had lost greatly in weight and strength during these weeks, 
and the entire period of convalescence consisted in obtaining an improve- 
ment of these conditions. The paretic disturbance of the left arm 
and hand persisted, but showed a slight improvement from week to 
week. 

During the following summer he was taken into the country about the 
Great Lakes, where he rapidly grew well. His father states that he left 
him there able to run about and paddle a canoe. The sole damage that 
remains is a tingling and stiffness in two fingers of the left hand. 



NEPHRITIS 



725 



§7 

To this list in which the patients recovered I add a note 
on some acute nephritides in which the patients succumbed. A 
first fatal case is abstracted as Case XXVII. 

Case XXVII. — (Dr. Elizabeth Campbell, Cincinnati, Ohio). Miss 
E. T., aged forty years, a school teacher, consulted her physician a month 
before entering the hospital because she was constantly tired. She was 
thin, but without other physical findings of an abnormal nature. The 
urine was entirely negative. She was given an iron tonic, and urged 
to take a rest and to increase the amount of her food intake. On this 
regime her general health improved. February 24, 1912, she entered the 
hospital complaining of a sore throat which had developed two days 
previously. Both tonsils were found enlarged and inflamed, and the 
lymphatic glands on both sides of her neck were swollen and tender. 
She suffered from pains in various parts of her body, and was nauseated. 
Her pulse was 112, and her temperature varied between 99.2° in the 
morning and 101.6° F. in the early evening. Her urine on the first 
half day after her entrance amounted to 300 cc, was dark amber, and 
acid, but free from albumin and casts. There was no oedema. She 
was kept at complete rest in bed on a milk and vegetable diet. 

By February 28 her throat had practically cleared, the neck glands 
had decreased in size, and her general symptoms had improved. Dur- 
ing this time she had taken frequent 0.3 gram doses of sodium bicarbonate 
with 0.25 gram doses of aspirin. Her temperature now varied between 
99° in the morning and 100.6° F. in the evening. Her pulse ran between 
96 and 112. On February 26 a trace of albumin was first noted in her 
highly acid urine as well as a few leukocytes. In the next two days the 
amount of albumin rose and granular, hyaline, and epithelial casts were 
noted. The urinary output per twenty-four hours was about 300 cc. 
At the same time diacetic acid and acetone in abnormal amount appeared 
in it. Sugar was absent as before. During these days the patient 
was frequently nauseated, and a marked generalized oedema developed. 

From February 28 to March 7 the patient's temperature steadily 
declined, so that on this day it was normal. Her pulse continued high, 
104 to 120. Beginning on February 28, 480 cc. of the following solution 
were administered daily by slow drip into the rectum: 

Sodium carbonate (Na2C0 3 - 10H 2 O) 10 grams 

Sodium chlorid 14 grams 

Distilled water, enough to make 1000 cc. 

The urinary output in twenty-four-hour periods after this regime 
was instituted ran as follows: 330+ cc; 480+ cc; 540+ cc; 725 cc; 
1080 cc; 1140 cc; 1050 cc; 1035+ cc. The urine remained acid all the 
time that these injections were given, and acetone and diacetic acid con- 
tinued to be present in abnormal quantities. The amount of albumin, 
4 which in the first three days of this period had been great, diminished 



726 



(EDEMA AND NEPHRITIS 



so that only a trace was noted in the later days. Medication during 
these days consisted of digitalin by hypodermic injection and occasional 
doses of strontium bromid at night. 

On March 7, when I first saw the patient, her general condition was 
so good that I merely approved of the scheme of treatment that was 
being followed out. The rectal injections of alkaline hypertonic salt 
solution were continued as before. The day previously the patient had 
been drowsy, nauseated, and had had headache, but at the time of my 
visit the headache was less severe. That night she slept well. The 
following day she was uncomfortable because of an accumulation of 
gas m the bowels. Her temperature was normal and the pulse 108. 
The evening of this day and in the night she vomited, though the rest 
of the night • she slept fairly well. During these two twenty-four-hour 
periods 1140 and 1275 cc. of acid urine were voided, containing only 
traces of albumin, very few granular casts, a few red and white blood 
corpuscles, and diacetic acid and acetone in excess. 

The morning of March 9 was uneventful, but in the afternoon the 
patient began to complain of nausea. At 6 p.m. she vomited. The 
nausea and vomiting continued and became severe in the night. At 
7 in the morning she complained of drowsiness; 1350 cc. of urine were 
voided in this twenty-four-hour period. 

At 7.30 a.m. (March 10) the patient was unable to swallow some 
proffered milk, and at 8 a.m. the nurse noted that the patient " had 
a far-away look in her eyes, and did not answer questions." Shortly 
afterward the breathing became labored. At 9.15 the nurse noted that 
the now unconscious patient looked constantly to the right, and at 9.30 
a convulsion occurred. The convulsions were very severe and lasting, 
and chloroform was administered to control them. Crepitant and 
subcrepitant rales could be heard throughout the chest. Two 10-drop 
doses of tincture of veratrum viride were given into the muscles of the 
thigh. 

At 12, with no feeling that anything could be accomplished thereby, 
1500 cc. of the alkaline hypertonic sodium chlorid solution were given 
intravenously. At 1.15, 300 cc. of urine were taken from the bladder 
by catheter, at 2.15 another 235 cc, and at 4.30 a final 75 cc. The first 
of these specimens, which included all the urine which had accumulated 
in the bladder since midnight, was heavily laden with albumin and casts. 
The second specimen contained relatively little albumin, the third 
again a large amount. All three specimens after the albumin had been 
removed reduced Fehling's solution heavily. The unconsciousness 
continued throughout the day, and the collection of fluid in her lungs 
increased. The patient could make no effort to cough it out, and the 
right to do a tracheotomy and practice insufflation was denied. Slight 
muscular twitchings were noted," but no more convulsive seizures. 
Oxygen played into the mouth helped but little. At 6 p.m., heavily 
cyanotic, the patient died. 

Autopsy performed immediately after death showed a well-marked 
oedema of the superficial tissues. The peritoneal cavity was dry. 



NEPHRITIS 



727 



The kidneys were somewhat swollen and of good color. The capsules 
stripped easily. The liver was smooth and somewhat swollen, the cut 
surface dry. The spleen was swollen so that the capsule was tense, 
but otherwise showed no changes. The pleural cavities contained a 
few ounces of free fluid. The lungs, crepitated throughout, were heavy 
and ran fluid from their cut surfaces. The apices showed some flat, 
thick scars in the pleura. The pericardial cavity was empty, the peri- 
cardium smooth. The heart muscle was flabby and slightly grayish. 
The endocardium was normal. Permission to open the head was not 
granted. 

In retrospect I feel responsible for the loss of this woman. 
In spite of the daily rectal injections of alkali, it is clear she did 
not get enough, as evidenced by the persistence of an acid reaction 
in her urine. I erred further on the day of my first visit in not 
completely ignoring her good urinary output, and directing all 
attention to the well-marked brain symptoms evident the day 
before. As I have previously said, the state of one organ as 
evidenced by its function is not an index in these cases of the 
state of another. The alkali and salt should have been more indus- 
triously pushed on the day of my first visit, and subsequently. 
The patient should, moreover, have been given an adequate 
amount of dextrose (glucose) by rectum or intravenously. Her 
small daily intake of food with persistence of diacetic acid and 
acetone in the urine clearly indicated that a starvation " acidosis " 
was being added to the other conditions conspiring to produce 
i her fatal brain cedema. 

§8. 

There~are certain types of acute nephritis in which the toxic 
agent is of a kind to lead to irreversible colloid changes in the 
kidney from the start and in which therefore a hope of relief 
is small from the outset. Bichlorid of mercury when absorbed 
in sufficient amounts belongs in this class, as does phosphorus. 
A number of my colleagues have nevertheless reported relief with 
ultimate recovery of the partial or complete suppression of urine 
in bichlorid poisoning. H. B. Weiss 1 has detailed astonish- 
ingly good results in some thirty odd hospital cases (with but two 
deaths) after employment of continuous sodium carbonate-sodium 
chlorid injections by vein or rectum, aided by the administration 
of potassium tartrate, sodium citrate and sugar by mouth. He 

1 H. B. Weiss: Jour. Am. Med. Assoc., 71, 1045 (1918). 



728 



(EDEMA AND NEPHRITIS 



finds, quite naturally, that early treatment is better than late. 
The same beneficent effects of alkali administration were observed 
in experimentally poisoned animals by William DeB. MacNider 1 
who is frank in declaring this and other types of heavy metal 
poisoning (uranium) an acid intoxication. In one of my patients 
alkali, salt, dextrose, and water failed to elicit any response. She 
was seen for the first time in the third day of her anuria. When 
after twenty-four hours of alkali, salt and sugar intravenously no 
urine came, I urged a decapsulation, hoping to find a swelled kidney 
into which no blood was passing because of compression of the 
blood vessels. Instead, the kidney was soft, gray and mottled in 
spots and streaks with yellowish- white areas of " fatty degenera- 
tion.'' 2 The patient lived for nine days, in the course of which 
she developed no generalized oedema or any signs of a "uremia." 
Her blood pressure was normal at first, but fell on the eighth day. 
The volume of her pulse also fell slowly, disappearing at the wrist 
some eight hours before death. As the blood pressure fell her 
pulse rate increased and she became dyspneic. In this state, still 
clear mentally, she died. 

Two cases of phosphorus poisoning in children who had sucked 
the heads off some phosphorus matches died in almost identical 
fashion, though the urinary suppression in these had never been 
absolute. 

These three fatalities teach that not everything, including 
death, occurring in an individual showing casts and albumin, 
is at once to be regarded as consequent upon the kidney condition. 
The patients died of a "toxic shock" analogous to the "toxemic 
shock" that carries them away after the more protracted types of 
infection. 

Early in the eclampsial series that I have seen, the follow- 
ing fatality occurred. The patient, practically at term, threw 
herself out of bed in a convulsion early one morning. She 
was brought to the hospital late at night after the convulsions 
and coma had lasted through the day. No urine had been 
obtained since the night before, and catheterization was dry. 

1 William DeB. MacNider: Jour. Exp. Med., "23, 171 (1916); Proc. 
Soc. Exp. Biol, and Med., 14, 140 (1917);. Jour. Exp. Med., 26, 1 (1917); 
ibid., 26, 19 (1917); ibid., 28, 50 (1918); ibid., 28, 517 (1918). 

2 For a discussion of what these changes mean physico-chemically see 
Martin H. Fischer and Marian O. Hooker: Fats and Fatty Degenera- 
tion, 9, 11, 76, New York (1917). 



NEPHRITIS 



729 



She was injected intravenously with 1600 cc. of an alkaline 
hypertonic salt solution at midnight. Her convulsions stopped, 
and she cleared mentally so that at 4 a.m. she talked to her 
nurse. Between midnight and 6 a.m. she passed 412 cc. of urine 
filled with albumin and casts. She had no labor pains. At this 
time she was given ether and a vaginal Caesarean section was 
performed. There was marked hemorrhage, and at 9 she died. 

It remains a question whether this should really be counted 
a failure. The fatality occurred eight years ago when I had 
less faith in the efficacy of a dehydration therapy and was less 
inclined than now to urge the quieter methods of delivery. The 
knowledge that an interruption of the pregnancy is synony- 
mous with a cessation of the intoxication is a constant argument 
in favor of speed. In looking at this side of the picture we 
forget all too easily that a third, and according to some statistics 
a half, of all the convulsive seizures occurring in pregnant women 
do not take place until after delivery, in other words, not until 
the tremendous acid production of the muscular efforts of labor, 
the anesthetic, the bleeding, the pain, and the necessary surgical 
procedures has been heaped upon that already incident to the 
pregnancy itself. The injurious consequences of all these must 
be subtracted from what we gain by speed before we obtain a 
correct estimate of the value of our therapeutic procedures. 

It is these facts that must also be kept in mind when the 
value of capsule stripping in nephritis comes up for debate. In 
at least some instances good has followed such a procedure. 
But this can be expected only if the deciding element between 
the recovery of the affected kidney and death is thought to be 
measurable in the increased circulation obtainable through the 
kidney by stripping the capsule. Even after the answer to this 
is given in the affirmative, then, before operating, the effects of 
the anesthetic and the shock of the operation must be con- 
sidered, and not unless these are taken to be negligible should 
it be done, especially since experiment and clinical experience 
thus far are entirely one-sided in showing that all that can be 
gained through operation can be gotten by the simpler dehy- 
dration means of adequate alkali, sodium chlorid, magnesium 
sulphate and sugar administration. 

These injections are also of service in surgical operations 
in which by accident or design the blood supply to the kidney 



730 (EDEMA AND NEPHRITIS 

is temporarily occluded. The consequences of such a procedure 
are those of the experiments - already detailed in which the blood 
vessels to the kidney were clamped. It has been shown by 
C. C. Guthrie 1 that perfusion with a physiological salt solu- 
tion or a Ringer solution of kidneys so treated affects them 
more deleteriously than if they are left alone. This is not because 
the sodium chlorid is poisonous to the kidney, as Lawrence 
Litchfield 2 has maintained, but because these salt solutions 
are not sufficiently concentrated and alkaline to prevent the 
swelling, etc., of the kidney cells. Most perfusion mixtures 
moreover lack the necessary colloids — the water in them is free, 
which is not the case in blood and lymph. 3 

§ 9 

A further recitation of cases could add little to what has 
been saici. I should only like to emphasize once more the 
additional aid offered by a liberal use of the carbohydrates. 
When a desire for food is obtainable by an appeal to the appetite 
so that the gastro-intestinal tract can be used in normal fashion, 
cereals of various kinds, with sugar and salt work excellently. 
Candy in various forms is frequently desired and may well be 
given. Buttered and creamed toast, grapefruit juice with sugar, 
milk with milk-sugar added, etc., all not only prevent but help to 
relieve from a chemical point of view the " acidosis" so frequently 
observed in patients ill of any of a large number of causes. 

When the normal route is inadequate or unavailable then 
the carbohydrate must be given by rectum or intravenously. 
But when this is done it must be given in an immediately utilizable 
form, in other words, as dextrose (glucose) of a high grade of 
purity. As several hundred grams are necessary to cover the 
daily demands of the resting adult individual, too much dextrose 
can hardly be given. In mild cases a continuous administra- 
tion of dextrose with alkali is easily accomplished by rectum. 
The alkali and sugar must never be mixed until immediately before 

1 C. C. Guthrie: Arch. Int. Med., 5, 232 (1910). 

2 Lawrence Litchfield: Jour. Am. Med. Assoc., 63, 307 (1914). 

3 These truths are all being rediscovered in these days. What G. H. 
Whipple, H. P. Smith and A. E. Belt (Am. Jour. Physiol., 52, 54, 72, 101 
(1920)) describe as "plasmapharesis," namely, the effects following bleeding 
succeeded by the injection of Locke solution containing red blood corpuscles, 
is simply hemorrhage complicated by the effects of "free water" upon the 
body cells when deprived of an adequate circulation. 



NEPHRITIS 



731 



injection, as the alkali decomposes the sugar, and it is best, as a 
matter of fact, to alternate the two. 

For intravenous use I give the dextrose alone. When alkali 
and salt are needed they are injected separately. In order to 
get as great a dehydrating effect as possible the sterilized dextrose 
solution is preferably given in highly concentrated form. Forty- 
five to ninety grams are dissolved in 100 to 200 cc. of freshly 
distilled water and injected very slowly (thirty minutes to an hour 
should be consumed) intravenously. To use haste is to lose the 
effect of the injection and to subject the patient to unnecessary 
risk. 

8. Dehydration Therapy in Other (Edemas 

Space does, not permit a detailed discussion of the problem, 
but it must be apparent to the reader that this same alkali, salt 
and sugar therapy may be advantageously used (and empirically 
has been used) in a number of other clinical states in which a 
generalized or localized oedema is largely responsible for the signs 
and symptoms observed. It has already been shown how in the 
treatment of nephritis (oedema of the kidney) the same measures 
which bring about an improved kidney function, simultaneously 
relieve the " uremia" (oedema of the brain). The allegedly 
" uremic" symptoms are, however, only the clinical manifestations 
of a swelling central nervous system which will explain why a 
proper dehydration therapy will relieve such symptoms even when 
the mechanism producing such oedema is one different from that 
commonly associated with kidney disease. Administration of 
alkaline hypertonic salt solution works well in the brain cedemas 
following injury, 1 alcoholism, 2 arsenic (salvarsan) injections, etc.; 
in the delirium, twitchings and convulsions seen in the acute 

1 W. B. Cannon (Am. Jour. Physiol., (1901)) showed these to be due to 
changes in the brain itself. He held the increase in intracranial pressure 
to be due to an increased water absorption dependent upon an increase 
in the osmotic pressure of the cell contents. Brain swelling is more cor- 
rectly interpreted as a colloid-chemical phenomenon. Cannon's work has 
scarcely received its merited recognition. Had it, we should have been 
spared much modern clinical and surgical teaching which still considers 
blood pressure the source of increased intracranial pressure. This is para- 
mount to regarding the former as a source for energy greater than itself, 
for the swelling brain is able to shut off its own arterial blood supply. 

A recent study of brain oedema in the terms of colloid-chemistry is that 
of J. S. Kopetzky (Trans. Am. Acad. Ophth. Oto-Laryn. (1913)). 

2 James J. Hogan: Jour. Am. Med. Assoc., 67, 1826 (1916). 



732 



OEDEMA AND NEPHRITIS 



infectious diseases; in the comas of arteriosclerosis, cerebral 
thrombosis and diabetes. Jau Dox Ball 1 has used such ther- 
apy in various mental states having observed the periods of 
agitation and of depression in patients siifTering from melancholia 
to be associated with an increase in blood pressure, their improve- 
ment with a fall. While originally inclined to attribute the 
changes in blood pressure to toxemic states influencing primarily 
the circulatory system, Ball 2 now believes that the increase in 
blood pressure is the response to an increased cerebral oedema. 
Decrease in this brain oedema then expresses itself not only 
through an improvement in mental symptoms, but in a fall of the 
blood pressure toward the normal. I have been informed that 
Haevey Cushixg and E. C. Cutler feed several teaspoonsful 
of table salt to their patients precedent to brain operations or 
afterwards, preventing in this way the tendency to cerebral hernia 
when the skull is opened. Their practice seems based on the 
similarly minded experimental studies of Weed and McKibbex. 3 
While these authors explain the effects of their injected hyper- 
tonic salt and baking soda solutions on an " osmotic " basis they 
are more logically corafrary to the brain swelling experiments 
which Marian 0. Hooker and I detailed in 1912. Could more 
direct proof be found of the clinical apphcabihty of the principles 
laid down in these pages? 

The continuous administration of mildly hypertonic alkaline 
solutions (baking soda solutions) and the carbonates of calcium 
and magnesium has also proved of sendee in scurvy; in angio- 
neurotic oedema; in the marasmus of infants and children; in 
bronchial asthma; it frequently relieves the labored breathing 
of arteriosclerosis 4 and heart disease. C. C. Fihe has obtained 
excellent results by using alkalies and salts in hay fever and 
mucous colitis, as has, in the latter condition, W. S. Kuder. 

When one deals with readily accessible oedemas.one can observe 
directly the good effects of alkali and salt when applied locally. 

1 Jau Don Ball: Am. Jour. Insanity, 68, 661 (1912). 

2 Jau Don Ball: Personal communication (1918). 

3 Lewis H. Weed and Paul S. McKibben: Am. Jour. Physiol., 48, 531 
(1919). 

4 Dyspnea in arteriosclerotics is most commonly due to the high acid 
content of the blood secondary to cardiac insufficieny. It may, however, 
be secondary to an oedema of the lung dependent upon arterial disease of 
the bronchial arteries, or an oedema (acid intoxication) of the medulla, 
itself dependent upon arterial change in the cerebral vessels. 



NEPHRITIS 



733 



A. E. Wright, J. L. Lohse 1 and James J. Hogan have long em- 
ployed alkaline hypertonic salt solutions (as 1 per cent sodium 
citrate and 2 per cent sodium chlorid, or 2 per cent sodium citrate 
and 1 per cent sodium chlorid) in all manner of superficial injuries, 
burns and infections as a wet dressing. 2 A saturated solution of 
magnesium sulphate produces a similarly agreeable dehydration 
of the tissues. This explains its long recognized virtues in reduc- 
ing swollen rheumatic joints, etc. One can by wet bandaging with 
either of these solutions easily reduce the oedema of a vulva, 
penis or scrotum as observed in heart or kidney disease or in con- 
junction with certain infections. John D. Long has injected 
solium citrate and similar salts into the oedematous tissues in 
acute and chronic joint affections and attributes more than theo- 
retical value to the observed reduction in swelling thus obtained. 
And have we not long recognized the agreeable effects of applying 
mild alkalies to flea bites, mosquito bites and urticarial wheals and 
the value of using alkalies and calcium chlorid internally? Is the 
reduction of these annoying oedemas any different from the reduc- 
tion by like means of those produced experimentally on gelatin 
plates? At the same time such experiences yield ocular evidence of 
just what we are trying to do to internally situated organs when by 
any means we increase the alkali and salt content of the body tis- 
sues by administration of such by mouth, rectum, or intravenously. 3 
The large number of clinical conditions, involving so large a 
variety of organs, in which an alkali and salt therapy proves of 
service may seem at first sight somewhat strange. Surprise will 
disappear if we remember that the observed changes are merely a 
response to " injury." Whether such was induced by chemical, 

1 J. L. Lohse: Lancet-Clinic, 107, 649 (1912). 

2 While I am not myself prepared to say that the antiseptic action of various 
dressing fluids is entirely without value, it is true that all the pure and derived 
hypochlorite (Carrell-Dakin) solutions of the war represent, as used, 
hypertonic alkaline mixtures. Those who have used sodium chlorid-sodium 
citrate solutions, for example, with the same surgical care as is employed 
when the hypochlorite mixtures are called into play pronounce the former 
not only less irritating and destructive to tissue, but as effective in the bac- 
teriological cleaning up of infected wounds. W. H. and N. B. Taylor (Jour. 
Am. Med. Assoc., 74, 1704 (1920) ). while holding that antiseptics "are not 
contraindicated " recommend 10% NaCl for wound irrigation which "does 
not waterlog tissues " and has furnished " the most phenomenal results." 

3 See in this connection the interesting experiments of Chiari and 
Januschke (Wien. klin. Wochenschr., 23, 12, (1910) ), who observed the oedema 
of the conjunctiva following instillation of mustard oil to be markedly de- 
creased or entirely suppressed through sufficient calcium administration. 



734 



(EDEMA AND NEPHRITIS 



thermal, mechanical, or other means, it is always associated with 
an abnormal production and accumulation of acid in the injured 
part, as clearly evidenced by the electrical change called the 
" current of injury." Most injuries to protoplasm are met by 
a reaction which in pathology is called " inflammation," 1 the most 
constant sign of which is, as we would expect, a " swelling " of the 
injured part, in other words, an cedema. 

9. On (Edema as an Alleged Consequence of Sodium Chlorid 

Retention 

It has been noted by different authors that in cedemas of various 
types, as in those associated with certain types of nephritis, with 
heart disease, etc., there is evidence of chlorid retention in the 
body. From this it has been quite generally concluded that in 
these conditions the kidneys are unable to eliminate chlorid (or, as 
ordinarily stated, are unable to eliminate sodium chloiid) and that 
its retention in the body is responsible for the oedema. Upon 
such reasoning has been based the widely approved therapy of 
sodium chlorid restriction, and since a lessening of cedema has at 
times been observed in patients following such restriction, the 
argument as a whole has been regarded as entirely sound. 

Against it have stood the failure of good observers to see 
any clinical improvement following careful efforts at apply- 
ing the principles of sodium chlorid restriction, and the experi- 
mental facts developed in this volume, which have all gone to 
show that the presence of salt, including sodium chlorid, in 
simple proteins, or in living cells, tissues, or organs always 
reduces the amount of water absorbed, either under normal 
circumstances or in states of abnormally great hydration (cedema) . 
These considerations have compelled the conclusion that sodium 
chlorid restriction as a scheme of therapy is not only wrong in 
principle but harmful in practice. 

It is the purpose of these paragraphs to indicate why sodium 
chlorid retention and cedema go hand in hand. Sodium chlorid 
retention is not due to an inability of the kidney to eliminate it, 
but to a change in the proteins (and other colloids) of the body as 
a whole. Sodium chlorid retention does not lead to oedema, but 
the changes which lead to oedema and to sodium chlorid retention 

1 For a stimulating discussion of the colloid-chemical changes of inflam- 
mation, see Paul G. Woolley: Lancet-Clinic, 109, 360 (1913). 



NEPHRITIS 



735 



are the same, consisting, in the main, of an abnormal production 
and accumulation of acid in the body. 

Proof of this may be brought from both a clinical and an 
experimental side. So far as the clinical aspects are concerned 
it is sufficient to emphasize that sodium chlorid retention is a 
constant accompaniment of all pathological conditions in which 
there is evidence of an abnormal production and accumulation 
of acid in the body, as betrayed through a persistently high 
hydrogen ion or titration acidity of the urine, an increased 
hydrogen ion acidity of the blood, an increased hydrogen ion 
acidity of the saliva or other secretions from the body, a high 
relative or absolute ammonia excretion in the urine, a low 
carbonic acid content of the blood or alveolar air, etc. 1 Because 
such acid intoxication is common to many different clinical 
states it is readily apparent why sodium chlorid retention 
has long been observed in pneumonia, in many of the infectious 
diseases, in the pernicious vomiting and intoxication of preg- 
nancy (eclampsia), in the cyclic vomiting of children, in diabetes, 
in carbohydrate starvation, in the severer types of the circulatory 
disturbances, in the severer anemias, in poisonings with arsenic, 
lead, phosphorus, chloroform, ether, and alcohol, and in the 
generalized parenchymatous nephritides when accompanied by 
a generalized oedema. The water retention likely to be observed 
in all these states is not secondary to the sodium chlorid retention, 
but both are due to the existent acid intoxication. The presence 
of acid in abnormal amount in the body not only increases the hydra- 
tion capacity of the (protein) body colloids, but it increases at the 
same time their capacity for holding chlorid. 

Experimental proof of this may be easily brought. When 
protein (carefully washed fibrin or gelatin) is thrown into a 
salt solution, it not only absorbs water from the salt solution, 
but salt as well. Upon adding acid, the amount of water absorbed 
is increased, but the absorption of salt is also increased. The 
presence of acid, in other words, leads not only to greater swelling, 
but also to sodium chlorid retention. Experiments were made 
by placing weighed amounts of fibrin or gelatin in definite volumes 
of neutral or acidified sodium chlorid or calcium chlorid solu- 
tions of definite strength kept in carefully stoppered flasks. 
After varying periods of time the solutions about the swollen 

1 See the succeeding pages 765, 778 and 790 (footnote). 



736 



(EDEMA AND NEPHRITIS 



protein were filtered off and the chlorid in them determined by 
titration with silver nitrate according to Volhakd's method. 
The following experiments will suffice to illustrate the values 
obtained : 

Experiment 101. — A dry gelatin plate weighing 0.813 gm. is placed 
in each of the following solutions : 

1. 75 cc. m/6 NaCl+25 cc. H 2 0. 

2. 75 cc. m/6 NaCl+25 cc. n/10 HN0 3 . 

Titration (of an aliquot portion) of the surrounding fluids 19 hours 
later shows the former to contain 0.00303 gm. CI ( =0.005 gm. 
NaCl) more than the latter. In other words, the gelatin in the acid 
solution has absorbed this amount of CI (or NaCl) more than the gelatin 
in the neutral medium. Twenty-three hours later the difference is 
still more striking. At this time the surrounding liquid in the first 
mixture contains 0.00606 gm. CI ( =0.01 gm. NaCl) more than the second, 
or, conversely expressed, this much more CI (or NaCl) has been absorbed 
by the gelatin in the acid medium than by that in the neutral one. 

Experiment 102. — Three grams powdered fibrin are placed in each of 
four flasks containing, respective^, the following solutions: 

1. 85 cc. m/8 NaCl+15 cc. H 2 0. 

2. 85 cc. m/8 NaCl+ 5 cc. n/10 HNO 3 +10 cc. H 2 0. 

3. 85 cc. m/8 NaCl+10 cc. n/10 HN0 3 + 5 cc. H 2 0. 

4. 85 cc. m/8 NaCl+15 ccn/10 HN0 3 . 

Nineteen hours later the excesses of CI absorbed by the fibrin in the 
acid solutions over and above the CI found absorbed in the neutral 
mixture were, respectively, 0.00303, 0.004545, and 0.010605 gm., or, 
recalculated in terms of NaCl, 0.005, 0.0075, and 0.0175 gm. 

Experiment 103. — Three grams powdered fibrin are placed in each 
of five flasks containing, respectively, the following solutions: 

1. 40 cc. m/6 NaCl+10 cc. H 2 0. 

2. 40 cc. m/6 NaCl+ 2J cc. n/10 lactic acid+7i cc. H 2 0. 

3. 40 cc. m/6 NaCl+ 5 cc. n/10 lactic acid+5 cc. H 2 0. 

4. 40 cc. m/6 NaCl+ 1\ cc. n/10 lactic acid+2| cc. H 2 0. 

5. 40 cc. m/6 NaCl +10 cc. n/10 lactic acid. 

Twenty hours later the excesses of CI absorbed by the fibrin in the acid 
solutions over and above the CI absorbed in the neutral mixture are, 
respectively, 0.0010605, 0.0037875, 0.006969, and 0.0113625 gm., or, ex- 
pressed in equivalents of NaCl, 0.00175, 0.00625, 0.0115, and 0.01875 gm. 

It has been customary in the modern writings on chlorid 
retention to assume that it is retained as sodium chlorid, and 



NEPHRITIS 



737 



it is for this reason that in the experiments thus far detailed 
we have recalculated the value of the chlorid retention in terms 
of sodium chlorid. Chlorid is, however, better retained by 
acidified protein than by neutral protein even when it is offered 
in other form. Experiment 104 demonstrates the increased 
chlorid absorption under the influence of an acid in the case of 
calcium chlorid. 

Experiment 104. — Three grams powdered fibrin are placed in each 
of five flasks containing, respectively, the following solutions : 

1. 40 cc. m/6 CaCl 2 +10 cc. H 2 0. 

2. 40 cc. m/6 CaCl 2 + 2j cc. n/10 HNO,+7i cc. H 2 0. 

3. 40 cc. m/6 CaCl 2 + 5 cc. n/10 HN0 3 +5 cc. H 2 0. 

4. 40 cc. m/6 CaCl 2 + 7£ cc. n/10 HN0 3 +2i cc. H 2 0. 

5. 40 cc. m/6 CaCl 2 +10 cc. n/10 HN0 3 . 

Twenty-four hours later the excesses of CI absorbed by the fibrin in the 
acid solutions over and above the CI absorbed in the neutral mixture 
are, respectively, 0.00303, 0.004545, 0.00606, and 0.010605 gm., or, 
expressed in equivalents of CaCl 2 , 0.004735, 0.0071025, 0.00947, and 
0.0165725 gm. 

It would take us too far afield to discuss why chlorid is better 
retained by protein in the presence of acid than in its absence. It 
is sufficient to point out that the observed behavior may be 
nothing but an isolated illustration of the adsorption of a dissolved 
substance by a colloid, 1 which, as is so frequently the case, is 
decidedly better when an acid is present than when it is absent. 

To this effect may perhaps, be added a chemical one, for 
there exists evidence that an acidified protein combines chemically 
with neutral salts in a way that the " neutral protein" does not. 

The increased amount of chlorid retained by proteins under 
the influence of acid is of a magnitude to cover easily any amount 
ever found retained by patients. Rarely are more than some 
10 to 15 gm. of (sodium) chlorid held in the body. Choosing, 
for illustration, Experiment 101 as a basis for calculation, we 
note that at the end of nineteen hours the acidified gelatin has 
absorbed an amount of sodium chlorid in excess of that absorbed 
by the neutral gelatin, amounting to 0.61 per cent of the original 
dry weight of the protein. At the end of another twenty -three 
hours the figure has risen to 1.22 per cent. If we choose the 

1 See pages 210 and 642. 



738 



(EDEMA AND NEPHRITIS 



very liberal figure that but one-fourth the normal body weight 
is dry substance (of which more than 95 per cent is colloid) this 
means that a man weighing 75 kilos, developing the ability to retain 
even 0.61 per cent more salt, is already able to retain 114 gm. of 
sodium chlorid, or if the higher figure is chosen, twice this amount. 

These experiments have also a general biological interest 
in connection with the question of the " permeability " of cells 
to different substances. It is scarcely conceivable that anyone 
will maintain gelatin discs or fragments of powdered fibrin to 
be surrounded by " membranes " and yet observations of the 
type described in these paragraphs when made upon living cells 
or tissues are constantly cited as " proofs " of the existence 
of " membranes " about cells and of their alterable " perme- 
ability." Thus, it has been argued that " living " cells are 
surrounded by " osmotic " membranes " impermeable " to 
sodium chlorid and to other salts, which become " permeable " 
upon the addition of acid or of substances which indirectly 
lead to a production and accumulation of acid in the cells (chloro- 
form, ether, potassium cyanid, etc.). Would anyone by similar 
reasoning maintain that gelatin plates and fibrin flakes lying 
in a " physiological " sodium chlorid solution are " osmotic " 
systems surrounded by " impermeable " membranes which be- 
come " permeable " to sodium chlorid when an acid is added? 

Perhaps these experiments will illustrate anew the fruitful 
consequences of the application of colloid-chemical principles 
to medical and biological problems. As they have proved 
adequate in the explanation of the many phenomena characteristic 
of water absorption they will also explain without contradiction 
the absorption and secretion of dissolved substances, 

10. On the Treatment of Anasarca and Ascites. Comment on 
the Sodium Chlorid Restriction Therapy 

§ 1 

A generalized oedema is so prominent a feature in many patients 
afflicted with nephritis that it becomes at times itself an object 
of treatment. From what has been said it is clear that this gen- 
eralized oedema is not to be considered a consequence of the kidney 
state as is so widely done, but that the " nephritis" is rather to be 
regarded as in good measure an oedema of the kidney and so as 



NEPHRITIS 



739 



part of the general process which gives all the rest of the body an 
increased water content. 

Since both theoretically and practically it is found that the 
swelling of the kidney may be reduced through salts, the rec- 
ommendation that the nephritic try to keep the salt concen- 
tration in his kidneys high follows as a matter of course. 

The thought naturally suggests itself that the same scheme 
of treatment may be extended to his general oedema. While 
such a course has for decades been approved of empirically, as 
evidenced by the use of saline purgatives, saline diuretics, etc., 
in the treatment of oedema, a marked reaction against the giving 
of salts in nephritis and in the oedemas accompanying it and 
other pathological disturbances has more recently set in. Of the 
scores of salts that might have been attacked in this way, sodium 
chlorid has been especially marked out, and to-day it is a widely 
accepted belief that the presence of this particular salt in the body 
is responsible for the retention of water and so the oedema of neph- 
ritis, of certain cases of heart disease, etc. Evidence in support 
of this view has been entirely clinical. 

From our knowledge of their general physico-chemical activ- 
ities it cannot be understood why sodium chlorid should, of all 
the common salts that are found in the living organism, act in this 
specific way. That, as a matter of fact it does not, seems to me 
proved conclusively by everyday experience and the experiments 
detailed in this volume. Does the butcher not complain because 
his meats shrink when he salts them? And neither in the normal 
nor in the oedematous animal does an increase in its salt con- 
tent, sodium chlorid' included, lead to an aggravation of the 
oedema. When rabbits are injected with progressively stronger 
solutions of sodium chlorid they lose progressively more water 
(shrink), 1 while frogs developing a generalized oedema in con- 
sequence of poisoning with uranium (uranium nephritis (!) 
with casts, albumin and diminished water secretion), absorb 
decidedly less water if treated with sodium chlorid and other 
salts than when not so handled. 2 These remarks hold for 
all the tissues of the body. Evarts Graham 3 showed me 
recently a pair of guinea pigs which had been subjected to 

^ee page 331. 

2 See page 260. 

3 Evarts Graham: Personal communication (1914); Jour. Exp. Med., 
22, 59 (1915). 



740 



(EDEMA AND NEPHRITIS 



the same degree of chloroform poisoning. One was subsequently 
treated with alkali and hypertonic sodium chlorid, the other 
not. On autopsy the kidneys and liver of the untreated 
one were swollen, dry and strongly mottled with grayish white 
patches of necrosis; those of the treated were of normal con- 
sistence, bled normally and showed less evident patches of 
destroyed tissue. 

The salts decrease oedema wherever found, including that of cer- 
tain types of nephritis, and sodium chlorid is no exception to this 
rule. 

§ 2 

How best to deal with the accumulations of fluid which so 
often occur in the peritoneal, pleural and pericardial cavities 
in the cedemas associated with heart lesions, kidney lesions, 
etc., is a matter to which colloid chemistry can also give answer. 
We know, of course, that a considerable ascites, hydrothorax, 
or hydropericardium may develop and disappear without ever 
assuming enough importance to demand clinical consideration. 
At other times, however, they become so great that they of 
themselves give rise to trouble or at least add additional burden, 
as through their pressure effects, to the circulation, respiration, 
etc. These so-called transudates . are identical with lymph and 
blood plasma, and it is for this reason that they may persist for days, 
weeks, or months in the body cavities being without absorbed. They 
are colloid solutions in which the solvent is bound to the colloid, 
and not until the solvent is rendered "free" can it be absorbed. 
When nature does not spontaneously remove them they can be gotten 
rid of only by tapping. 

That this is true is borne out not only by our previously 
described experiments 1 but by the well-known fact that blood 
and lymph extravasations into the peritoneal, pleural or peri- 
cardial cavities, whether encountered in man or produced in 
entirely healthy animals, remain here unchanged and undi- 
minished in amount for periods of time in which other aqueous 
solutions not containing such colloid material (which, in other 
words, contain " free " water) are readily absorbed. The fol- 
lowing experiments prove this : 

1 See page 305 and the first edition of my "(Edema." See also James 
J. Hogan and Martin H. Fischer: Kolloidchem. Beihefte, 3, 385 (1912). 



NEPHRITIS 



741 



Expeeiment 105. — A black and white rabbit is taken from its 
hutch, catheterized, and then weighed. Its weight is found to be 
1493 grams. A slight opening is made in the abdominal wall and 
traction made on this so as to make the entrance of fluid into the 
peritoneal cavity easy. A second rabbit has the carotid laid bare for 
as great a distance as possible in the neck. It is ligated high up, an 
artery forceps is attached to the coat of the vessel, a small forceps 
is placed below this, and the carotid is severed. This second animal is 
now placed in such a position that the blood will flow directly from 
its carotid into the abdominal cavity of the first animal, when the 
forceps is removed. The blood passes in a stream directly from the 
cut artery of the second animal into the peritoneal cavity of the first. 
This procedure is carried out at 2.40 p.m. The abdominal wound 
is closed immediately and the animal is weighed a second time to see 
how much blood has flowed in. The second weighing registers 1504 
grams, which means that 11 grams of blood have flowed in. At the end 
of an hour the animal is killed by a blow on the head and immediately 
autopsied. The blood is found uncoagulated in the folds of the intestine. 
It is carefully aspirated into a tared flask and weighed. 11 grams of 
blood are recovered. 

Experiment 106. — In an entirely similar way a guinea pig, weigh- 
ing 520 grams, has a small opening made in its abdomen, and the blood 
from the carotid of a rabbit is made to flow directly into it. An increase 
in the weight of the guinea pig of 2.3 grams is thereby brought about. 
At the end of 1^ hours the pig is killed by a blow on the head and the 
unabsorbed blood is aspirated into a tared flask. 2.1 grams are recovered. 

Experiment 107. — A black and white rabbit, weighing 1630.5 
grams, receives intraperioneally in the already described way enough 
blood from the carotid of a second rabbit to raise the weight of the for- 
mer 26 grams. At the end of an hour the rabbit is killed, and the 
unabsorbed blood is carefully recovered by aspiration into a tared 
flask. 26 grams of blood are recovered. 

Experiment 108. — A white rabbit, weighing 767 grams, receives 
intraperitoneally 45 grams of blood from the carotid of a Belgian 
hare. At the end of seventy minutes the animal is killed by a blow on 
the head and the blood found in the peritoneal cavity is aspirated into a 
tared flask. 42.2 grams are recovered. 

There is nothing strange in the fact that the removal at times 
of a comparatively small amount, say of an ascitic accumula- 
tion, may be followed by a rapid absorption of the rest. As the 
amount of fluid in a serous cavity increases, the circulation 
through the surrounding tissues becomes more and more em- 
barrassed, and so the possibilities for absorption progressively 
poorer. To relieve this pressure even somewhat improves the 



742 



OEDEMA AND NEPHRITIS 



circulation, not alone as to quantity, but as to quality of blood 
passing through the part (a blood more nearly arterial in 
character replacing a highly venous one). By thus favor- 
ing the removal of carbonic and other acids always found in such 
serous accumulations 1 the power of the colloids here for holding 
water is decreased, and so further opportunity for the abstrac- 
tion of water from the transudates found in these cavities is 
brought about. What holds for the " transudates " and their 
absorption holds also, of course, for the absorption of inflam- 
matory " exudates." 

Various authors have claimed that the administration of 
sodium chlorid (and other salts) is bad practice because it 
increases the accumulations of fluid in the serous cavities in the 
cedemas encountered in " parenchymatous nephritis," in heart 
disease, etc. How the salts may be effective in this regard is 
explained by the following. When any salt is given an cedematous 
individual his tissues give up water as do the frogs that have 
been described. But where does the water go? The body 
weight as a whole can diminish only if this water is lost from 
the body through the urine (skin, gastro-intestinal tract, or 
lungs). But in a generalized nephritis and in heart lesions the 
kidney does not so readily rid the body of water as in health, 
and so this freed water must go somewhere else. If it does 
not come out through some other emunctory (as in watery stools 
or sweat) this water can only escape into the cavities. What 
happens is identical with what is observed in experimental 
animals when they are made to give up their water very rapidly 
(especially after first rendering them cedematous by any means 
we choose) by injection of concentrated salt solution. 

I saw a good clinical illustration of the process in a patient 
of W. S. Kudek. A woman who for several weeks had been in 
bed, suffering from an extensive generalized oedema, with col- 
lections of fluid in the pleural cavities and abdomen, secondary 
to a heart muscle insufficiency of several years' duration, had the 
abdominal effusion removed by paracentesis. In order to keep 
up the drainage some strands of silk were left in the opening 
made by the trocar. Seepage stopped at the end of twenty- 

*G. Strassburg: Pfliiger's Arch. 6, 65 (1872); A. Ewald: Arch. f. 
(Anat. u.) Physiol., 663 (1873); Felix Hoppe-Seyler : Physiologische 
Chemie., 1, 601, Berlin (1877). 



NEPHRITIS 



743 



four hours, but the silk was left in place. On the third day a 
liter of water containing 14 grams of sodium chlorid and 10 grams 
of crystallized sodium carbonate (Na2C03 • IOH2O) was given 
intravenously to combat the tissue cedema. This went down 
enormously, and as it disappeared the abdominal wound began 
to seep once more so that pad after pad had to be applied to 
absorb the liquid. James J. Hogan observed the same in a 
ten-year old child with a practically complete suppression of 
urine following an infection of the kidneys, in which a drain was 
left in the abdomen following paracentesis for an ascites. 

It is clear, therefore, that while the cedema of the tissues is 
reduced when salts (or alkali) are given an cedematous individual, 
the collection of fluid in the cavities may be increased. The 
thirst consequent upon the dehydration may lead the patient 
to drink water. In this way his total body weight (which in 
turn is taken as a measure of his cedema) may at times actually 
increase. 

But such a secretion of fluid into the peritoneal or other 
cavity is not by itself a particularly serious thing, for water and 
various salt solutions are readily absorbed from the peritoneal 
(and other serous) cavities. If the effects are lasting it can 
only be because the added fluid has given rise to more permanent 
changes through added pressure, etc., or because it has had colloid 
material added to it (albumin) which after secretion renders the 
water unabsorbable. It is of interest to recall, after what was 
said regarding the origin of albumin in the urine, that the ascitic 
fluid may be looked upon as an albumin-containing secretion from 
the peritoneal tissues which, in its general composition and mode 
of origin, finds an analog in the highly albuminous urine secreted 
by the kidney in acute nephritis. Syneresis and a "solution" of 
previously solid colloids occur in both. 1 

How now, if these views are correct are we to explain the good 
results reported by Widal and his school when patients with 
cedema are salt restricted. When the salt is taken out of the diet 
of a patient his appetite for water is tremendously decreased. If the 
patient is put upon the Karell dietary regime, care is taken from 
the start to assure not only a low salt intake, but a low water intake 
also. It is this water restriction in both cases that produces the 
reduction in oedema. 

1 See pages 283 and 508. 



744 



(EDEMA AND NEPHRITIS 



We ordinarily overlook the fact that even under normal circum- 
stances more than half the total water excretion is lost through the lungs 
and skin. Against the normal of, say, 1500 cc. of water lost as 
urine, man loses 500 cc. from his lungs, and 1000 to 2000 cc. through 
his skin. If the patient is in a warm room, or if he is warmly 
covered, or if, as is so frequently done, he is sweated, then these 
figures rise still higher. Even a completely anuric individual 
therefore suffers a substantial loss in weight if for any reason his 
water intake is restricted. But no colloid mass, be this a drying 
gelatin plate or a water-starved human being, loses its salt to the 
atmosphere as rapidly as it loses its water. The salts therefore 
become more concentrated in the cells and tissues of the body. 

To realize what must be the effect of all this upon the total 
body weight is not difficult. Successive daily weighings will 
show such a patient to be losing a kilo or more a day, and this 
is exactly what these clinical observers report. What a good 
effect this or any other effective dehydration scheme must have 
upon a nephritic kidney, a swelled brain or any similar condi- 
tion, can easily be appreciated when the vicious circles that 
may and do become established in any of these organs or in an 
extremity are kept in mind. I have repeatedly emphasized 
how an cedematous organ, not given free play to swell, tends to 
make itself progressively worse. As the organ swells, a ham- 
pering capsule, bony walls, or a small foramen make the swelling 
tissues compress the blood vessels entering the affected organ, 
and so a lack of oxygen, in itself capable of producing an oedema, 
is added to the already existing factors responsible for such. 
Thus, sweating, drink restriction, or salt restriction (which 
indirectly amounts to drink restriction) all lead to a drying out 
of the tissues. If now a kidney in its process of swelling, say 
from an intoxication of some sort, has succeeded in rendering 
itself anuric by squeezing upon its blood supply, a more normal 
state may once more be attained if we rob the body tissues 
and fluids of their water content, and so also draw upon the 
water content of the swollen kidney. The net result must be a 
better blood supply through the kidney, and if the initial insult 
to the kidney was not too severe or of too lasting a character, 
the restitution of a better circulation may well be equivalent 
to a relief of the kidney condition — just as when alkali and salt 
are gotten into this organ. 



NEPHRITIS 



745 



Then why not the salt restriction scheme of therapy? I would 
answer that salt restriction constitutes an unnecessarily round- 
about and by no means pleasant way of accomplishing a water 
restriction which can better be obtained by direct means. Second, 
as previously emphasized, intoxication depends upon concentra- 
tion. We can dull the effects of an intoxicant only by diluting it, 
and since we can guard ourselves against the bad effects of water 
by giving with it properly chosen salts in the right concentration, 
I have not been able to see the superiority of waiting for nature to 
dehydrate an organ which we can dehydrate as well and more 
rapidly, especially when in the former case we rob our patient of 
the advantage of having water available with which to float off 
his poisonous products. 

I should like to re-emphasize a last point in this entire matter 
of alkali, salt, and water therapy. It must be remembered 
that no solution is either absorbed or secreted as such, but that 
in every case the water and dissolved: substances move inde- 
pendently of each other, at times in the same direction, at others 
in opposite directions, and usually at entirely different rates. 
A primary purpose in giving the hypertonic solutions that I 
have advised is to secure an increase in the salt concentration in 
the body. Now the body cells and fluids in any state associated 
with an cedema have an increased capacity for holding 
water, and so take up water more easily than do the normal. 
The (edematous individual will therefore absorb* water from any 
given salt solution more easily than will the normal individual. A 
solution, " hypertonic" for a normal individual, may be "iso- 
tonic " for one whose colloids have an increased hydration capacity. 
So it need not surprise us to find that when even a strongly 
hypertonic salt solution is given certain nephritics they 
may show an initial increase in their cedema. This only means 
that the colloids of their tissues were not previously saturated 
with water. Neither does it prove that the salt injected was 
.responsible for this cedema, but only that the concentration of the 
salt which we succeeded in attaining in the body was not sufficiently 
high to decrease the existent high hydration capacity of the colloids 
of those tissues which showed the increased swelling. To remedy 
the situation we must give still more salt. (And at this time, 
as at all other times when we are trying to increase the absolute 
salt concentration in the body, we must give with the salt as 
little water as possible.) 



746 



(EDEMA AND NEPHRITIS 



XII 

■ 

DIAGNOSIS AND PROGNOSIS IN NEPHRITIS 
1. Judging the Nephritic. Prognosis 

While the preceding pages will have made clear the meaning 
of the various signs and symptoms associated with the nephritic 
state and their significance for prognosis I am going to repeat here 
in rather dogmatic terms various facts because of their clinical 
importance and because I am constantly questioned regarding 
them. 

§ i 

What, first, may be learned from urinalysis 1 in nephritis? 
The great truth to remember is that urinalysis enables us to follow 
the course of pathological changes which may be occurring in a kidney 
and nothing else. The most serious mistakes both in prognosis 
and treatment which the physician can make are dependent 
upon his attempts to judge from urinary findings alone whether 
his patient is going to develop "uremia," increased blood pressure, 
etc. — all of them things in no way consequent upon the kidney 
disease. The possibilities for such complications must be discovered 
by other clinical methods. 

With this fact firmly in mind, it is of primary interest to dis- 
cover whether the kidneys are functionally competent or not. 2 
Any kidney which in putting out a satisfactory amount of water 
and in which such secretion may be maintained is functionally com- 
petent. Use the ability of a kidney to put out water as the index to 
the amount of kidney substance not involved in a pathological process; 
the number of casts and quantity of albumin as an index to the amount 
that is involved. 

Practically expressed, the 24-hour urinary output should be 
determined. If the amount runs above 1000 cc. (34 ounces) it 
may be assumed that sufficient kidney function is left to be con- 
sidered adequate. Any amount of urine above this daily liter is' 
to be considered in the patient's favor so far as his kidney function 
is concerned. This is true even of the "chronic interstitial" 

1 Space does not permit a discussion of the urinalytic methods most 
important for the general man in medicine or surgery and their significance. 
I have done this elsewhere (see Martin H. Fischer: Practical Urinalytic 
Methods, Tice's Practice of Medicine, 1, 423, New York (1920) ). 

2 See page 757. 



NEPHRITIS 



747 



nephritic whose kidneys are rarely (and then only terminally) 
physiologically inadequate. 

If the water output falls below a liter daily it does not yet mean 
defective kidney function — it may simply be the result of excessive 
sweating, great catharsis or low fluid intake. The patient 
should therefore be given a half liter (16 ounces) of water to drink. 1 
If the urinary secretion is definitely increased (by 400 to 500 cc. 
or 13 to 14 ounces) in the succeeding two hours (or certainly upon a 
second testing in similar fashion during a subsequent two hour 
period) the prognosis is favorable. If no such increased diuresis 
results the entire gamut must be run of causes lying (1) without or 
(2) within the kidney which may be responsible for such lack of 
function. 

§ 2 

What now does the discovery of casts and of albumin (of kidney 
origin) in the urine tell us? It merely tells us that destruction is 
occurring in the kidney and nothing more. It tells us nothing of 
the nature of the destroying forces nor of their importance from 
the standpoint of the patient. This information has to be worked 
out by other methods than urinalysis. Speaking generally , large 
numbers of casts and much albumin mean greater destruction than 
a smaller number with little albumin. Yet so far as the patient is 
concerned either finding may be of trivial or of great importance. 
The occasional cast with a trace of albumin may be of great 
importance if it is the expression of blood vessel disease, but not 
because of the kidney findings but because of the accompanying 
diagnosis of blood vessel disease. On the other hand, large 
numbers of casts with albumin in an active athlete or in a man who 
works to the point of becoming dyspneic (as in running for cars, 
making close connections, hard walking, etc.) may mean nothing, 
for any healthy man may get into such a state and over it in a few 
hours. Similarly, a man whom we first see in a convulsion and in 
whose urine we then discover casts and albumin must not at once 
be called a " chronic interstitial nephritic " the subject of a 
" uremic" attack. He may be such, but a convulsion from any 
cause (which really only means hard muscular work with respira- 
tory interference) as an epileptic fit, the spasms of strychnin 

1 See page 760. 



748 



(EDEMA AND NEPHRITIS 



poisoning, or those consequent upon an infection, will put casts 
and albumin into a urine that never contained them before. 

Only if no such temporarily acting factors are at work are an 
increase in casts and albumin to be regarded as significant. 
The nephritic who with bed rest and proper treatment shows 
increasingly larger quantities of casts and albumin, is certainly 
not getting better, but good judgment must be used before it 
is stated too flatly why the patient is getting worse. Especially 
is restraint in order before any change in the patient's general 
condition is said to be due to the more evident signs of kidney 
involvement. More casts and more albumin in the urine mean, 
of course, more kidney involvement, but only clinical judgment 
can say whether the added factors lie within the kidney itself 
or outside of it. A progressing blood-vessel disease may involve 
larger and larger areas in the kidney up to the whole organ; 
or an infection originally limited to a spot or a few spots may 
spread to involve the whole kidney. But all too often, especially 
in the so-common chronic interstitial nephritides associated 
with blood vessel disease, the increase in the casts and albumin 
coincides with the time the patient gets out of the ambulatory 
class, and the causes for the increase lie entirely outside of the 
kidneys. A failing circulation is discovered — a failing heart 
muscle with dilatation, leaking aortic and other valves, dilata- 
tion of the aorta itself, etc.- — and the prognosis for the patient 
becomes that of his circulatory disturbances with little emphasis 
upon the kidney findings which in ioto are now so largely dom- 
inated by and secondary to the heart failure. 

It is a safe rule whenever confronted by a patient showing 
simultaneously the signs of heart disease and of kidney involve- 
ment to look upon the heart as the greater offender and not 
the other way around, as is so often done. The matter is of 
much importance from the standpoint of clinical diagnosis, 
prognosis and treatment. The problem is often brilliantly 
illustrated by some of the so-called " orthostatic " cases of 
albuminuria. Many of these are really undiagnosed cases of 
cardiac insufficiency. Such patients may not show a single 
abnormal urinary feature when at bed rest, but the increased 
work incident to mere maintenance of the upright position for 
an hour or two make albumin and casts appear and continue as 
long as the upright position is persisted in. In the ambulatory 



NEPHRITIS 



749 



nephritic presenting cardiac signs or symptoms or, to turn it 
about, in the cardiac patient showing albumin and casts in the 
urine I make use of the simple expedient of two or three days' 
rest in bed by way of estimating and eliminating the cardiac 
element in the production of his urinary signs. Many a patient • 
with valvular disease, whose heart is efficient for certain low 
degrees of physical endeavor and in whom the cardiac process is 
not of a progressive type may be taught how to live and be 
given a more cheerful outlook upon life by not having a diag- 
nosis of " Bright's disease " superadded. 

But the impression must not be gotten from these remarks 
that a cardiac element is the only one which accounts for the 
orthostatic types of albuminuria, nor yet that all which is 
eliminated by bed rest is of cardiac origin. The blood of an 
anemic individual may supply his kidneys when at rest in bed 
with enough oxygen to keep the urine free from albumin, but 
prove inadequate when he assumes the erect posture with its 
increased need for oxygen; or kidneys which in the prone posi- 
tion are freely supplied with blood may yield albumin and casts 
because their blood vessels are dragged upon when the patient 
rises. 

§ 3 

The urinary findings are of much service in determining whether 
a generalized or a spotty type of nephritis is at hand. An involve- 
ment of the whole kidney brings with it a decrease in urinary out- 
put with many casts and much albumin; a normal water output 
with less albumin and casts obviously means that some of the 
kidney substance has escaped injury (for less than one-fourth the 
total kidney substance is sufficient to maintain the normal water 
secretion, and the albumin and casts are proportionate to the 
amount of substance that is being destroyed). A low water out- 
put should therefore lead to the diagnosis of generalized kidney 
disease (generalized parenchymatous nephritis); a normal (or 
increased) water output to a diagnosis of a spotty affection (infec- 
tious nephritis, chronic interstitial nephritis) with the amount of 
spotty involvement judged from the number of casts and amount 
of albumin. In the first instance search must be made for factors 
which are capable of thus affecting a whole kidney ; in the second 
for such as can give rise to spotty types of disease. 



750 



(EDEMA AND NEPHRITIS 



Practically, the first calls for a recognition of all the causes 
capable of producing a generalized poisoning of the whole kidney, in 
the list of which may therefore be found the old " predisposing' 1 
guard of cold, hard work and a high protein diet; the more direct 
factors of heart disease, respiratory disease, hemorrhage or 
anemia; the direct kidney poisons beginning with the volatile 
and fixed anesthetics, passing through the heavy metals and 
ending with the soluble protein products produced through infec- 
tion or through pregnancy (intoxication with foreign protein 
derived from the sperm?). 

The diagnosis of such a generalized kidney disease is greatly 
aided by the discovery of oedema elsewhere in the body and the 
absence of any increase in blood pressure. (If there is an increase 
in blood pressure it must be determined whether this is due to an 
oedema of the brain or to vascular disease.) 

The spotty type of nephritis has behind it either (a) an infec- 
tion of the kidney or (b) vascular disease. The former again 
carries with it no increase in blood pressure. The most significant 
diagnostic point indicative of this type of kidney disease is the pres- 
ence of leucocytes in the urine. The ordinary toxic types of ne- 
phritis (following heart lesions, mercury or arsenic poisoning, etc.) 
and the so-called chronic interstitial types associated with high 
blood pressure do not show appreciable numbers of white cells in 
the urine. To recognize the kidney associated with vascular 
disease the whole patient must be seen. The increased blood 
pressure, obvious vascular changes and cardiac hypertrophy being 
the real elements upon which a correct diagnosis is made. What 
is most important in this tj r pe of kidney disease is to remember that 
practically none of the things of which the patient complains or is 
the victim have anything whatsoever to do with the kidney 
disease. The urinary findings tell what is happening in the kidney 
and nothing else. If these are satisfactory the kidneys may be 
passed. If the patient is ill or dies, he is not dying of kidney 
disease. A normal or "increased" water output never means 
anything but good kidney function and the occasional cast and 
trace of albumin mean that very little kidney is undergoing 
destruction. There are no "masked" nephritides or "uremias 
without urinary findings." There are only deaths in patients in 
whom vascular disease may have affected the brain or heart or 
some other vital organ while leaving the kidneys untouched. 



NEPHRITIS 



751 



§ 4 

As previously noted, the oedema observed in a sufferer from 
nephritis is never to be regarded as secondary to the kidney 
disease. In generalized parenchymatous nephritis the general 
cedema is simply due to the same cause as the oedema of the kidney. 
In the earlier stages of the chronic interstitial types of nephritis 
associated with vascular disease we are not in the habit of expect- 
ing an cedema. When these patients do show such it means exactly 
what a generalized cedema always means — a generalized intox- 
ication of some type. Such may be any of the many kinds 
which overwhelm the previously normal individual, but in actual 
practice their origin, in the chronic interstitial types with blood 
vessel disease, is almost always traceable to something which can 
interfere with the normal (oxidation) chemistry of the whole 
body. The commonest of these are disturbances affecting the 
general circulation or respiration, wherefore careful consid- 
eration of the heart and its efficiency is not only demanded, 
but usually reveals the real source of the trouble. As a con- 
sequence of the cardiac disturbance with its resulting gener- 
alized oedema is to be expected an cedema of the kidneys whence 
the increased casts and albumin and the decreased urinary out- 
put. The patients with chronic interstitial nephritis associated 
with vascular disease rarely die of their kidneys. Exclusive of 
the fatal accidents which may overtake anyone and which are 
especially prone to attack the vascular case, as hemorrhage, 
thrombosis, coronary disease, etc., they die almost half and half 
of failing hearts which will not supply enough blood to keep 
the remains of their kidneys working, or of cedemas of the brain 
secondary to the vascular disease (and wrongly called "uremias"). 
The prognosis of chronic interstitial nephritis associated with vascu- 
lar disease is almost entirely the prognosis of vascular disease and of 
heart efficiency. 

§ 5 

Exactly as our judgment of the chronic interstitial nephritic 
cannot rest too exclusively upon certain kidney findings, so 
also will their too intense contemplation in the parenchymatous 
types lead us into false paths. While in rare instances the kid- 
neys may be picked out alone to exhibit the picture of a gen- 



752 



(EDEMA AND NEPHRITIS 



eralized parenchymatous nephritis, an intoxication is commonly 
at the root of the process, which affects simultaneously all the 
organs of the body. Hence the so common association of the 
oedema of the kidney with an oedema of all the tissues of the body. 
Yet the one is not the consequence of the other, and so we may 
see complete suppressions of urine without a degree of surface 
cedema that can be recognized clinically, or a generalized (toxic) 
oedema in which the eyes are swollen shut, the skin stretched and 
shining, the ringers and toes swollen until they stand apart, 
and yet no urinary findings; or such developing after the gen- 
eralized cedema has persisted for days. The cedemas of the 
different organs are each to be sought for in turn and their 
intensity and importance judged alone from the point of view of 
the organ in which they occur. An cedema of the medulla (naUsea, 
vomiting, Cheyne-Stokes breathing) or brain (headache, stupor, 
coma, convulsions, delirium, "insanity") is more important than 
one of the kidney, and this than one of the liver. An oedema 
of the optic nerve is not dangerous to life, but, if persistent, 
destructive to vision. Many times the same degree of swelling 
in the skin has no lasting consequences. 1 

§ 6 

The variations from the normal blood pressure bring much 
clinical light, but no quick statements regarding their meaning 
can safely be made. The kidneys may be almost or com- 
pletely destroyed without the slightest increase in pressure. It 
may safely be said that the generalized parenchymatous nephritis 
due to a poison or to an infection of the kidney never alone 
increases the pressure. Early in some intoxications and infec- 
tions there is a slight rise in blood pressure because of their effects 
upon the circulatory system, but when they persist they almost 
always lead to a gradual decrease in blood pressure (ending in 
the general picture of toxic or toxemic shock). A heightened 
or even very high blood pressure may be observed in patients 

1 Exactly as the albumin content of the urine rises in cedema of the 
kidney (nephritis) the albumin content of the cerebro-spinal fluid rises in 
cedema of the brain or cord. Edmund M. Baehr first called my atten- 
tion to the high protein content of the spinal puncture fluid in three 
"uremia" cases. The care necessary to avoid the trap of a wrong diag- 
nosis of brain syphilis on the basis of such findings is self -apparent. 



NEPHRITIS 



753 



having parenchymatous nephritis, but not because of this. 
The pressure is nearly always the expression of brain oedema. An 
increasing or high blood pressure in the intoxication of pregnancy, 
for example, points not to kidney disease, but to a developing brain 
ozdema due to the same poisoning which is producing such kidney 
signs as may be present. 

Except for such causes of high blood pressure as these in 
patients showing abnormal urinary findings, a high blood pressure 
is most commonly due to blood vessel disease or certain types 
of heart lesions. Of the two, blood vessel disease is, of course, 
the commoner offender. A high blood pressure with cardiac 
enlargement, a few casts and albumin, when an old primary heart 
lesion can be ruled out, calls for a primary diagnosis of vascular 
disease. The maintained high blood pressure in such patients 
is not in itself to be regarded as a bad sign, — it may mean a well- 
marked vascular involvement, but it also means good heart 
muscle. After the accidental variations due to work, excitement, 
etc., have been taken into consideration, a rising blood pressure 
usually means progress of the vascular disease or development 
of a brain oedema. A falling blood pressure is good when we can 
trace it to improvement in the vascular disease, but when such 
is not there, it becomes too often the sign of a failing heart muscle. 
It should also be remembered that a high systolic pressure alone, 
while it means a good heart muscle, does not yet mean an effective 
circulation of the blood. The diastolic blood pressure must be 
correspondingly high. A low diastolic blood pressure means 
that the effect of the systole in moving the blood forward is being 
largely lost, and the finding of an aortic lea*k or a dilating heart 
too commonly explains why it exists. 1 

These considerations render it clear why, in the so-called 
chronic interstitial types of nephritis, therapy should be directed 
primarily toward the relief of the blood vessel condition so far 
as such may be possible,. and toward the maintenance of an 
effective heart action. To relieve the symptoms of the patient 
and to reduce the blood pressure, persistent, daily administration 
of sufficient alkali to keep the urine constantly neutral is un- 
doubtedly the most effective single thing we can do. Arthur 
D. Dunn came to this same conclusion entirely independently. 

1 See in this connection the interesting studies of Willard J. Stone: 
Jour. Am. Med. Assoc., 61, 1256 (1913); Lancet-Clinic, 111, 247 (1914). 



754 (EDEMA AND NEPHRITIS 

It is remarkable how the high blood pressure will fall and 
remain low. As attempts to meet the vascular disease itself 
may be listed (because of my belief in its infectious origin) the 
approved hygienic means generally considered effective in com- 
bating such, as fresh air, rest, and good food, or when syphilis 
is suspected, iodids, mercury and arsenic preparations in addi- 
tion. To bring aid to a distressed heart the use of digitalis and 
other cardiac stimulants, even though they raise the blood pres- 
sure, have long been known to be of service. Such therapeutic 
measures yield better results than the drastic dietary restrictions 
or the empirical incantations so often invoked over this long- 
suffering group of patients. 

It is apparent also why measures which merely reduce 
blood pressure (except in cases of hemorrhage) are not only 
disappointing in their results, but may actually do harm. 1 I 
have several times seen alarming falls in the urinary output 
and once a complete suppression of urine with death of the patient 
eight days later after the administration of nitrites to reduce 
blood pressure in cases of chronic interstitial nephritis associated 
with vascular disease. Suppression of urine is bound to follow 
the lack of blood supply thus induced to kidneys which are already 
barely getting enough with a high blood pressure. There is 
no justification for giving nitrites in chronic interstitial nephritis 
unless we can show that while reducing general blood pressure 
we are not at the same time reducing the blood supply to the 
kidney to a dangerous point. 

And yet these considerations must not be interpreted as an 
interdiction of the use of nitrites in all clinical conditions. When 
we deal with symptoms referable to vascular disease or " vascular 
spasm " affecting particularly but one organ, as in angina 
pectoris, the nitrites may well be tried in the hope of obtaining 
a vasodilatation in the affected organ without losing enough 
in other organs to do harm. But whether we will or will not 
get such an overplus of good effects can be determined only 

1 D. M. Ervin (Jour. Am. Med. Assoc., 70, 1208 (1918) ) found that the 
administration of blood pressure lowering drugs (nitroglycerin) in patients 
brought into the hospital in convulsions, precipitated new attacks, while the 
administration of blood pressure raising drugs (epinephrin) prevented such. 
Ervin holds that the convulsion comes on whenever the blood pressure falls 
below the intracranial pressure. Proper treatment, obviously, should try 
to reduce the intracranial pressure. 



NEPHRITIS 



755 



by careful observation of the individual patient when such 
vasodilators are first tried. 

§ 7 

We should not fail in looking for the factors capable of pro- 
ducing the acid and similarly acting substances which we hold 
to be directly responsible for the development of the signs and 
symptoms of a nephritis to consider foci of infection. 

After we have eliminated cold, hard work, heart disease, the 
poisonous products of pregnancy, bichlorid of mercury, arsenic, 
etc., as the possible first causes of a nephritis, the infections loom 
up as the next most important factors, especially in the more 
persistent forms of this disease. The parenchymatous neph- 
ritides that do not clear after bedrest, alkalinization and a liberal 
diet (like the pregnancy intoxications that do not clear with 
proper treatment five to ten days after delivery) or the spotty 
types (either the infectious nephritides in children or adults or the 
vascular types in maturer individuals) which show signs of get- 
ting worse should all be examined and with the greatest care for 
points of infection. The practitioner (and the specialist as well) 
should learn that in this field negative findings do not count. 
Disease is never "idiopathic" and it does not progress without 
cause. Our own abilities may be inadequate to discover them 
but that these things have beginnings and that their first causes 
have not been eliminated if they show signs of progressing — of 
this there can be no doubt. Hence the importance of searching 
for foci of infection in the tonsils, teeth, ears, and mastoids; in 
the sinuses of the head and face; in the genito-urinary tract of 
men and women, as well as elsewhere in the body. The causal 
connection between such points of infection and the signs and 
symptoms of a nephritis with its alleged consequences is often 
brilliantly demonstrated by the clearing up of long-standing cases 
of albuminuria, by a persistent fall in a long standing high blood 
pressure, by an improved general circulation, by a disappearance 
of " uremic" headaches, etc. How comparatively trivial and 
constantly neglected foci of infection lead to toxic and destructive 
changes in many of the organs of the body (including the kidney) 
has been beautifully demonstrated by the clinical, bacteriological 
and experimental studies of the Chicago school (Frank Bill- 
ings, Edward C. Rosenow, E. R. Le Count, Rollin T. 



756 



(EDEMA AND NEPHRITIS 



Woodyatt, D. J. Davis, Ernest E. Irons, Wilber E. Post and 
their collaborators). 1 

§ 8 

The above remarks may serve, I trust, to make it clear that 
what is of importance to the victim of "chronic Bright's disease" 
is not his vibration between no albumin and a fraction of a gram to 
the liter of urine, but the general estimate of the progressiveness 
or non-progressiveness of his disease with time and under the 
influence of the advice of his regular, medical father confessor. 
Recourse to Latin terminology, bedside debate of the importance 
of "coefficients" (the nature of which is hardly understood by 
the authors who produced them), the hash of fact and fancy which 
those of us who have authority pass off as "science" — these 
things mean nothing to a patient and nothing to the physician 
who must care for him for months or years after we have had him 
a week. The value of any therapy in "Bright's disease" has 
been judged too much from a few badly made and ultra-refined 
analyses of the urine while a patient was spending ten days with 
us in a city hospital. What we really want to know is how good 
the therapy is when the patient is spending ten years with his 
doctor at work in the country. 

With these facts in mind, which show how the whole patient 
and not only his kidneys must be seen if we would judge rightly 

1 To the long list of "metabolic" diseases already eliminated by these 
workers we must, I think, add gout. In five patients — 4 men and 1 woman 
— falling strictly within the text-book type of the disease (nocturnal big 
toe attacks, urate tophi in ears and skin, unsymmetrical urate deposits in^ 
finger joints, susceptibility to nucleo-protein feeding, etc.) badly infected 
teeth were observed in all. Two have recovered absolutely since losing all 
their teeth. A third who would develop "gouty" attacks whenever his teeth 
were " cleaned " by a dentist is better. The remaining two still have their 
teeth — and their gout. May we not better regard these patients as suffering 
from embolic infectious arthritis with the urate deposits secondary thereto 
and analogous to the formation of "stones" in infected gall bladders, kid- 
neys or urinary bladders? The same infectious embolism in other organs 
will then explain the alleged consequences of gout, as the occasional fever, 
the muscular involvement, the nephritis, the occasional leucocytosis, etc. We 
are only slowly beginning to learn the multiplicity of pathological effects 
exerted by one and the same organism when grown under different environ- 
ments. See in this connection the fundamental work of William B. Wherry: 
Jour. Inf. Dis., 2, 436 (1905), cholera red reaction; Arch. f. Protistenkunde, 
30, 77 (1913), flagellation of amebae; Centrabl. f. Bakt,, Parasitenk. u. 
Infektionskr., 70, 115 (1913), "spore" formation in tubercle bacilli; Jour. 
Inf. Dis., 13, 114 (1913), acid proofness in tubercle bacilli. 



NEPHRITIS 



757 



the meaning of his urinary findings, we shall consider next the 
meaning and value of some methods which have been resorted 
to by way of determining kidney efficiency. 

2. Underlying Principles and Clinical Value of Kidney 
Efficiency Tests 

Clinicians have for many years and in many ingenious ways 
tried to determine the physiological efficiency of different organs. 
How valuable would be at times a correct knowledge of the 
working power of the heart, of the chemical activity of the liver, 
of the secretory activity of a kidney is, of course, obvious, 
and yet the bitterness of controversy which surrounds the various 
attempts that have been made to estimate such scientifically 
suffices to indicate how far we are still from the desired goal. 
Before my own position in the matter, so far as the kidney is 
concerned, is expressed, I would emphasize the necessity of 
bearing in mind some physiological truths, the ignoring of which 
has led to the expectation of obtaining by efficiency tests on 
different organs impossible ends, or to a condemnation of such 
as have real, even though rather limited, value. 

With the exception of certain portions of our central ner- 
vous system it is characteristic of our organs that they each 
contain several times as much material as is necessary to meet 
the work requirements of every day. Seven-eighths of our pan- 
creas may become functionless and still enough internal secre- 
tion be obtained to keep us from becoming diabetic; the work 
demands on the heart may be trebled or quadrupled and yet 
it goes on; half or three-quarters of the liver may be destroyed 
with no signs of a hepatic insufficiency. Similar claims 
may be made for each of the organs of the body. We possess, 
in other words, a potential power many times that actually used. 

The important corollary of this fact is that an organ 
continues to show a normal function as long as more than such a 
physiologically necessary minimum remains preserved, even though 
large pieces of it may actually be temporarily functionless or 
totally destroyed. The more definitely more than such a phy- 
siological minimum is still preserved the less can any ordinary 
test give us an inkling of the actual amount of damage. The 
test has to be heightened to the point of straining all of the normal 



758 



(EDEMA AND NEPHRITIS 



or imagined remnants of an organ before a defect here will 
manifest itself. These considerations hold for the functional 
testing- of all organs. How they apply to the specific problem 
of the kidneys is evident from what follows. 

The mystic element of human nature is well expressed in 
its so commonly voiced faith that it is the function of the kid- 
neys to excrete the poisons produced in the body. Such a view 
ignores the fact that they are quite as likely to be excreting 
substances for a lack of which the animal is perishing, as when 
in salt starvation they continue to secrete this even though its 
lack in the body is killing the animal. But however we may 
choose to look upon such obvious facts, it is evident that the 
kidney's ability to give off dissolved substances may serve as one 
type of kidney efficiency test. To most this has appeared the 
only test, and yet we need but recall that a dry kidney can get 
rid of nothing at all to show how its ability to give off water is 
really quite as important, in fact, as previously emphasized, 1 
it is the primary function of the kidney, and the secretion of all 
dissolved substances is secondary to this. The efficiency of a kidney 
may therefore be gauged by its ability to secrete water. Before 
discussing the utilization of these considerations in clinical practice, 
some animal experiments in which we have conditions under better 
control than in our clinical practice had best be borne in mind. 

The best way to do away with any amount of organ function 
is to remove parts of the organ. In the case of the kidneys it is 
an easy matter to take away three-fourths and even more of the 
total substance and yet have the animal live. Such removal 
means, of course, a loss of three-quarters of the normal kidney 
function. Animals so operated upon excrete water and all dis- 
solved substances, such as the various dyes, exactly as do normal 
animals. Even excessive amounts of water given such animals 
by way of placing " strain " on the remaining portion are 
easily cared for. The important conclusion to be drawn from 
this is that mere loss of three-quarters of the normal kidney function 
(and even more) does not yet betray itself to any of our ordinary 
functional tests. This fact is of great clinical importance because 
it means that ordinary efficiency tests tell us nothing until we 
are working on the last quarter or less of our total kidney efficiency. 
Efficiency tests, as we shall see, still retain a useful purpose in. 

1 See page 368, 



NEPHRITIS 



759 



spite of this, though it might as well be emphasized now that 
when we are thus working on the last elements of a still function- 
ing kidney obvious clinical signs will in most cases tell us quite 
as much. 

It is well now to re-emphasize that the secretion of dis- 
solved substances is secondary to the secretion of water, not 
in the sense that if a liter of urine brings out a gram of dissolved 
substance two liters will bring out two, but in the physico-chemical 
sense 1 that if no water at all is secreted into the uriniferous 
tubules no dissolved substance at all can be washed out of the 
kidney parenchyma and therefore none be secreted. If some 
water comes through then some dye comes out also, while with 
more water more dye will be washed along. But the time that 
the water remains in contact with the parenchyma plays an 
important part in permitting diffusion, etc., wherefore the con- 
centration of the dye may be greater with less urine than with 
more, but other conditions the same, the absolute amount never. 

The increased output of any dissolved substance when, other 
conditions remaining the same, the amount of water passing 
through the kidneys is increased, has for half a century been 
one of the well established facts of physiology. Experimenting 
upon himself C. Genth, 2 for example, found that during a con- 
trol period he voided a daily average of 1252 cc. of urine with 
40.2 grams of urea. In a subsequent period when everything 
was kept constant except that an added two liters of water were 
consumed he secreted 3250 cc. of urine with 46.6 grams of urea. 
When the water intake was increased to four liters the urine 
rose to 5500 cc. and the urea to 54.2 grams. Similar results are 
obtained if the observation periods are measured by hours instead 
of days. 3 While such increases have been quite generally 
attributed to an increased " protein metabolism," they probably 
represent pure washing-out processes, for upon return to the 
original water intake the urea excretion falls not only to the nor- 
mal, but for a period to a figure even below this. What has 
been said here of urea holds also for the total urinary nitrogen or 

1 See pages 206, 367 and 640. 

2 C. Genth: Ueber den Einfluss des Wassertrinkens auf den Stoffwechsel, 
Wiesbaden (1856). 

3 Oppenheim: Pniiger's Arch., 23, 4B5 (1880); see also Neumann: 
Arch. f. Hyg., 36, 248 (1899). 



760 



(EDEMA AND NEPHRITIS 



some of its other fractions, as ammonia, creatin, 1 creatinin, and 
alantoin. 2 It holds also for such salts as sodium chlorid. 3 

The whole matter is easily demonstrated on animals with nor- 
mal or reduced kidney substance. With ordinary feeding, rabbits 
eliminate 55 to 70 per cent of a dye (1.5 milligram phenolsul- 
phonephthalehO in the two hours following its introduction 
intramuscularly, but if the water secretion is heightened by 
intravenous injection of salt solution n5 to over SO per cent will 
be obtained. While the concentration in the individual samples 
of urine in the latter case is lower than in the former the absolute 
amount given off is not. With plenty of water coming through 
the kidney the dye also appears earlier than when such is not the 
case. Exactly the same occurs in patients. With little water 
coming through the kidney the output of potassium iodid, of 
milk sugar, of sodium chlorid, of a dye, etc.. is lower than when 
the same test is repeated on the same patient, but a heightened 
water secretion is assured by a greater water intake. 

I have been told that J. Alberrax first taught that a " poly- 
uria " following the administration of water was the best 
evidence of a patient's kidney efficiency. Alberrax's original 
communication is not accessible to me. but it expresses a view with 
which I heartily concur. I have never seen a patient showing a 
normal water secretion who did not also show a normal output of 
any of the dissolved substances customarily used in kidney tests. 

To have a water, or any other type of kidney test mean any- 
thing, it is evident that all the factors outside the kidney which 
are capable of influencing it must be eliminated as far as possible. 
If , for example, we do not get a normal water response this does 
not at once mean that the kidneys are affected. The patient's 
body colloids may not have been previously saturated with 
water, or exercise may have temporarily increased their water- 
holding power, or a circulation may be so defective that the 
blood never becomes properly arterialized and so " free " water 
for urinary secretion appears only slowly in it. 

To eliminate as many of these factors as possible it is nec- 
essary in making efficiency tests on a patient to put him at bed 

• C. C. Fowler and P. B. Hawk: Jour. Exp. Med.. 12, 3SS (1910). 

: L. T. Fair hall and P. B. Hawk: Jour. Am. Chem., Soc. 34. 546 

(1912). 

3 S. A. Rrxox and P. B. Hawk: Arch. Int. Med.. 7. 536 (1911). 



NEPHRITIS 



761 



rest for at least twenty-four hours and let him have an unre- 
stricted diet. The best time to make a water test is two and 
one-half hours after breakfast or two hours after the last water 
was drunk. It takes a normal person about this time to elim- 
inate whatever free water exists anywhere in his body. When 
this state has been attained, but not one beyond this in which 
the tissues are beginning to dry out, the patient empties his 
bladder (or if absolutely necessary a catheter may be inserted) 
and 500 cc. of drinking water are consumed. A normal person 
(or one having what will be called a normal kidney efficiency) 
excretes 400 to 500 cc. of the consumed water in the next two 
hours. The excretion shows an optimum point at the end of about 
an hour. The results of a few actual tests will show how the 
curves run. 

TABLE CXXIX 



Urinary Output in cc. 



Time in 
minutes 
and 
hours. 


Normal. 


Vascular disease with 
high blood pressure, 
cardiac hypertrophy, 
no heart murmurs, 
casts and albumin 
constantly in urine. 


Infection of kidney (un- 
known type). Casts 
and polymorphonuclear 
leucocytes from the 
kidneys constantly in 
urine. Occasional slight 
rises in temperature. 
No abnormal findings 
in rest of body. 


One kidney removed 
for infection. Re- 
maining kidney has 
shown large num- 
bers of casts, leuco- 
cytes .and albumin 
for several years. 






Test 1 


Test 2 







.15 


25 


40 


19 


20 


37 


.30 


50 


48 


31 


31 


43 


.45 


76 


119 


65 


59 


43 


1.00 


72 


148 


119 


96 


53 


.15 


62 


51 


128 


92 


59 


.30 


65 


44 


78 


58 


54 


.45 


57 


34 


47 


25 


49 


2.00 


28 


26 


29 


23 


42 


Total . . . 


435 


510 


518 


405 


380 



A secretion of water above the total of the 500 cc. consumed 
is usually attributable to the fact that free water over and above 
that administered existed in the body at the time the test was 
started. If a patient consumes water against instructions, or 
if in the digestion of his food considerable amounts of water are 
freed, these quantities are, of course, added to the 500 cc. admin- ^ 
istered. Similarly, a low secretion does not at once mean an 
involvement of the last quarter of the total kidney substance. 



762 



(EDEMA AND NEPHRITIS 



It may simply mean that the patient was not saturated with 
water and calls for an immediate repetition of the test. As the 
first administration of water ordinarily suffices to saturate the 
body colloids the second test is usually more reliable than the first. 

We need not specially emphasize that the outcome neither of 
the water test nor of any other functional test depends solely 
upon the functional ability of the kidney. A heart lesion, 
extensive interference with the respiration, etc., may all give rise 
to a deficient water output, and yet the kidney itself be but 
little affected. Neither do any of these tests tell us what is the 
pathological background for the disturbance in the kidney. 
They only tell us if the functional capacity has fallen below a 
certain minimum, regardless of the fact whether this disturbance 
is of a type which in a few hours will be removed, or is due to 
permanent destruction. 

I make it a rule to use with the water test one of those 
in which the elimination of a dissolved substance is followed, 
and the well wprked out phenolsulphonephthalein test of J. T. 
Geraghty and L. G. Rowntree 1 is perhaps the simplest and best 
of these. Geraghty and Rowntree provide for an adequate 
water secretion in their test in advance by having the patient 
consume several hundred cubic centimeters of it. While I lay 
greatest stress on the water secretion capacity of a kidney and 
have never .found one which if it would eliminate water would 
not also eliminate a dissolved substance, the use of a dissolved 
substance capable of rapid elimination, as phenolsulphonephtha- 
lein, along with the water test furnishes a valuable check. If a 
kidney is functioning well, but the water elimination is low 
due to some accidental factor such as insufficient water consump- 
tion, the disproportionately higher elimination of the dye at once 
betrays the fact, for the dye is washed out of the kidney by very 
little water. The real significance of the low water excretion due 
to such accidental factors is therefore immediately disclosed. 

A set of observations on the excretion of phenolsulphone- 
phthalein and other dyes in experimentally induced nephritides, 
interesting because of their bearing on the interpretation of clinical 
findings, has recently been made by 0. Schwarz. 2 He finds that 

1 J. T. Geraghty and L. G. Rowntree: Jour. Am. Med. Assoc., 57, 
811 (1911); 60, 191 (1913); 61, 939 (1913); Arch. Int. Med., 9, 284 (1912). 
2 0. Schwarz: Pfliiger's Arch., 153, 87 (1913). 



NEPHRITIS 



763 



when the acid content of the body is increased (resulting, as we 
have previously seen, in a retention of water and a diminished 
urinarj' output with casts and albumin in the urine) phenolsul- 
phonephthalein also fails to be excreted. Edward B. Reeme- 
lin and Raphael Isaacs 1 observed the same fact in dialysis 
experiments on blood. Blood serum holds fast to phenolsul- 
phonephthalein when acids are added to it. Under similar cir- 
cumstances the blood colloids also retain urea (non-protein 
nitrogen). In perfusion experiments on the kidney Isaacs 2 was 
able to show that lack of water secretion, reduction in phenol- 
sulphonephthalein, chlorid and urea output, and appearance of 
albumin in such "urine" as was secreted all followed increase of 
the acid content of the perfusing liquid, while a reduction in this 
led to opposite results. The acid variations were, moreover, 
slight, all lying within the ranges observed " physiologically." 

These findings are such as would be anticipated on the colloid- 
chemical basis. They teach at the same time how important are 
the extrarenal factors in determining secretion of water and 
dissolved substances from the kidney. Phenolsulphonephthalein, 
chlorids and urea are subject to the distribution law as are all 
other dissolved substances, and so under the influence of acid, 
salts, etc., are taken up or rejected by protoplasm elsewhere in 
the body as they are in the kidney. 

Clinical parallels to these experimentally demonstrable facts 
are common. I need but state that in the acuter types of heart 
failure the excretion of phenolsulphonephthalein, urea (" non- 
protein nitrogen"), chlorids and water all drop at once, to rise 
again as soon as the heart recovers. Here the whole body, 
and incidentally the kidney, is suffering from a lack of oxygen 
with its accompanying abnormal production and accumulation 
of acid. How -much more important it is in this illustration to 
recognize the heart lesion than the incidental kidney involve- 
ment needs no emphasis. Schwarz has, moreover, brought 
experimental proof of what was predicted theoretically. After 
acid injection (with its accompanying nephritis) some dyes are 
excreted even better than normally. 3 

1 Edward B. Reemeltn and Raphael Isaacs: Am. Jour. Physiol., 42, 
163 (1916). 

2 Raphael Isaacs: Am. Jour. Physiol., 45, 71 (1917). 

3 See page 640. 



764 



(EDEMA AND NEPHRITIS 



If these considerations are borne in mind it will serve to 
explain why I hold that the best evidence of kidney efficiency is 
its ability to excrete water. A kidney capable of secreting water 
is secreting in proper fashion everything else, and as long as suf- 
ficient water is supplied the patient and comes through, his state is 
not to be attributed to defective kidney elimination. This is true 
even of the alleged "uremias" encountered in chronic interstitial 
nephritis. The ability of a kidney to put out water may safely be 
used as an index to the amount of kidney substance not involved in 
a pathological disturbance; the number of casts and' amount of 
albumin as an index to the amount thus involved. 

The use of dyes in testing kidney efficiency finds its greatest 
service, perhaps, in dealing with one-sided kidney lesions. While 
ureteral catheterization will give us the water output from 
each of the two kidneys it is not devoid of danger. Cystoscopic 
observation of a properly chosen dye coming freely from one 
ureteral opening while little or none of it is coming from the 
other often suffices to betray the almost functionless character 
of one of the kidneys. 

The use which may be made of functional tests is self-evident. 
They are neither to be condemned as universally as they have 
been by some writers, nor yet to be regarded as alone capable 
of giving a correct index of the state of the kidney, as assumed by 
others. Except in one-sided kidney lesions where it is important 
to determine, as before surgical interference, the functional 
capacity of the kidney to be left, very evident clinical symptoms 
usually suffice to let us know when we are working on the last 
quarter (or eighth) of our total normal kidney capacity. When 
with adequate water supply by mouth a kidney secretion remains 
persistently low, mere measurement and examination of the 
twenty-four hour output suffice to tell us of the state of the kid- 
neys, and functional tests will not add much. The claims of 
some authors who have felt it possible to predict the onset of 
" uremic" attacks and death in patients with chronic interstitial 
types of nephritis from their low output of some dissolved sub- 
stance through the kidney need to be restudied. As previously 
emphasized, animals and patients deprived of their kidneys 
do not die as do those which clinically we diagnose " uremic." 
These " uremic" deaths are due to oedemas of the brain, and 
such are secondary, not to loss of kidney function, but to vascular 



NEPHRITIS 



765 



disease, to thromboses of the cerebral vessels, and to hemorrhage. 
Patients with chronic interstitial nephritis associated with blood- 
vessel disease die once in three times of a failing heart. And 
since individuals with uncompensated heart lesions fail to excrete 
water and dissolved substances exactly as do such as have their 
kidneys primarily involved, it may well happen that death 
is correctly prognosticated in such from a low dye output, but, 
to repeat, the death is again not due primarily to kidney disease, 
but to cardiac involvement. 

3. On Acidity Measurements of the Urine 

Such stress has been laid upon the importance of an abnormal 
production and accumulation of acid in various organs of the 
body in giving rise to an oedema in them, or in the case of the kid- 
ney, in leading to the development of the signs of a nephritis, 
that the question naturally arises whether we cannot in some 
way measure this acid content by way of getting an index to the 
severity of the changes occurring there. We have not at present 
any methods which can be used clinically for measuring changes 
in the acid content of the different organs in the body. Various 
attempts have been made to measure the acidity of the blood 
and these all show that in oedema and nephritis it is increased. 
The findings are, however, open to much question. 1 Reliable 
data on the acidity of the different secretions from the body, 
as the urine, the saliva and the sweat are, however, at hand, 
and other things remaining the same, the laws of chemical 
equilibrium then permit us — from the acidity changes in these 
secretions — to conclude that there must have been similar 
changes in the tissues from which they came. Thus an increase 
in the acidity of the urine means, generally speaking, an increase 
in the acid content of the kidney from which it came, and vice 
versa. By following the changes in acidity of some or all of the 
secretions from the body we may therefore obtain valuable clin- 
ical suggestions as to the severity of an acid intoxication in the 
body and an index to the efficacy of treatment with alkalies, 
etc. 

1 See the next section, page 775. 



766 



(EDEMA AND NEPHRITIS 



§ 1 

We have first to say exactly what we mean by urinary "acid- 
ity." In the days before physical chemistry the acidity or the 
degree of acidity of such a secretion as urine was usually measured 
by titrating it with an alkali of known strength. This gives the 
so-called titration acidity of the liquid, and this type of analysis 
has been applied to the urine, as to many other fluids derived from 
the body. The titration acidity of the urine in nephritis has by 
scores of investigators been found to run much above that of 
normal urine and we may still use it to advantage in studying our 
clinical cases to-day. A titration which for clinical purposes is 
sufficiently accurate, can easily be made by adding to 25 cc. of the 
urinary sample one or two drops of a 0.5 per cent solution of phen- 
olphthalein in 50 per cent alcohol and then titrating with one- 
tenth normal sodium hydroxid until a permanently pink color is 
obtained. While the capacity of the urine for thus neutralizing 
alkali varies throughout the twenty-four hours (being lowest just 
after meals and highest before meals, after exercise and through 
the night) normal urines, when mixed, twenty-four hour specimens 
are compared do not take up more than 20 to SO cc. of one-tenth normal 
sodium hydroxid per 100 cc. of urine. It must at once be clearly 
understood, however, that this titration acidity of the urine is not 
an absolute guide to the degree of acid intoxication occurring in a 
kidney. The reasons for this are obvious. When, for example, 
we compare the poisonous effects upon the tissues of equivalent 
concentrations of phosphoric acid, ammonium dihydrogen 
phosphate, diammonium hydrogen phosphate, and triammonium 
phosphate, the first is found to be highly poisonous, the second 
more mildly so, and the third and fourth still less poisonous, 
in the order named. Yet the titration acidities of all four as 
ordinarily determined by titrating with standard sodium hydroxid 
solution give the same reading. These facts must be kept 
in mind when judging the clinical significance of the titration 
acidity of the urine. For, clearly, were a urine filled with pure, 
highly poisonous phosphoric acid instead of the comparatively 
innocuous dibasic or tribasic salt, the titration acidity would not 
betray this fact. 

Determination of the titration acidity is nevertheless of great 
value if what has been said be kept in mind. It is capable of 



NEPHRITIS 



767 



giving us definite evidence of the existence of an abnormally high 
acid content in the urine (and therefore in the kidney) and of the 
changes in this from hour to hour or day to day. The trouble 
is that in actual clinical practice titration methods are scarcely 
used, or when used they are not employed often enough to give 
any adequate check on the short period variations in the chemical 
state of the patient. This is, of course, because titrations take 
time — more time than is ordinarily at the disposal of the 
practicing physician. Titration acidity does not, however, vary 
directly as the degree of intoxication, and only ignorance of the 
elementary facts of chemistry would ever lead anyone to expect 
such complete parallelism. 

§ 2 

The physical chemists have more recently distinguished 
between the latent and the active acidities of a fluid, meaning 
by the first the total replaceable hydrogen, by the second the 
hydrogen ions yielded upon solution in water. When the 
physical chemists speak of acidity they usually refer to the active 
or hydrogen ion acidity, and a large portion of them believe that 
all so-called acid effects are dependent exclusively upon the 
presence and the number of these hydrogen ions. When the 
acid content of a system is increased there follows usually an 
increase in the hydrogen ion acidity. Increasing the amount 
of acid in a beaker of water is followed by an increase in the 
number of hydrogen ions, and when we deal with very dilute 
solutions the increase in hydrogen ion acidity is very nearly 
proportional to the increase in the amount of acid. It is for this 
reason that the hydrogen ion acidity of urine coming from a kid- 
ney containing a more than usual amount of acid, as in nephritis, 
is usually increased. The increased acid content of the kidney, 
to satisfy the laws of chemical equilibrium, demands an increased 
acid content in the urine coming from it, and as an expression 
of this we find an increased hydrogen ion acidity. The hydrogen 
ion acidity of the urine can be measured in various ways, and 
since some of these can be used clinically it constitutes one 
figure of value in judging a kidney case. 

It must, however, be clearly understood from the outset that 
hydrogen ion acidity determinations of the urine can alone be no 
absolute index to the severity of the intoxication occurring in the kid- 



768 



(EDEMA AND NEPHRITIS 



ney, nor yet that every increase or decrease in hydrogen ion acidity is 
or must be followed by a corresponding increase or decrease in the 
severity of the intoxication in the kidney. The reasons for this 
are, of course, perfectly obvious. The attempt was made some 
twenty years ago to show that the toxicity of various acids, as 
determined by their effects upon growing plants, the sense of 
taste, the absorption of water by muscle, the aggregation of 
infusoria, etc., followed their degree of ionic dissociation. It was 
early learned, however, that no such parallelism exists. Thus, 
it was found that acetic and other organic acids with their low 
dissociation produced physiologically as great effects as the 
highly dissociated hydrochloric, nitric, and other acids. On the 
other hand, the rather highly dissociated sulphuric acid produced 
physiological effects far below the weakly dissociated organic 
acids. In other words, physiological effect is not determined 
solely or even in the main by the degree of dissociation. I believe 
I was the first to show that an entirely similar disproportion 
between degree of ionic dissociation and effect produced holds 
for the swelling of various protein colloids, and in so doing 
emphasized that the observed physiological reactions depend, 
in the main, upon the protein constituents of the tissues under 
consideration. ! 

It would, therefore, have been manifestly absurd for me 
ever to have claimed that any physiological effect could be 
measured by merely determining quantitatively the hydrogen 
ion acidity, and this whether we deal with purely physiological 
reactions or with the question of the development of the signs of a 
nephritis in a kidney. An increase in the hydrogen ion acidity 
of the urine above a normal standard may serve as evidence of 
an abnormal acid content in the kidney itself, but it can never be 
a complete measure of the degree of the intoxication. To make 
the matter more concrete we need but illustrate this by saying 
that on poisoning a kidney with hydrochloric acid there occurs 
a great increase in the hydrogen ion acidity of the urine, yet if 
we produce a similarly great intoxication by the use of lactic 
acid only a slight rise is observed; on the other hand, intox- 
ication with sulphuric acid again gives us a great rise in hydro- 
gen ion acidity, and yet comparatively little effect on the kidney. 

To these considerations needs to be added the further fact, 
which I have so often emphasized, that an increase in the acid 



NEPHRITIS 



769 



content in such an organ as the kidney does not alone determine 
the degree of effect produced. The presence and kind of salts 
found in a protein influence markedly its swelling and solution, 
and mere measurement of the hydrogen ions in the urine tells 
us nothing of these factors. As a matter of fact, the addition 
of salt (even of neutral salt) to an acid protein mixture brings 
about an actual rise in hydrogen ion acidity of the liquid about 
the protein as this shrinks. The same fact can at times be 
observed clinically when a temporary rise in the hydrogen ion 
acidity of the urine follows the active administration of salt 
alone. Unless such simple principles of physical and colloid 
chemistry be borne in mind we shall never come to a correct 
understanding of the value and limitations of such hydrogen 
ion determinations. 1 

1 By ignoring what I have written here and in my previous books and 
papers L. J. Henderson and his co-workers, W. W. Palmer and L. H. New- 
burgh, have wasted energy in attempts to disprove what I have never 
said. My constantly reiterated claim that certain changes in tissues are 
due to an " increased acid content " cannot at will be made to read by 
these authors an " increased (hydrogen ion) acidity." The latter may 
under otherwise constant conditions become evidence of the former, but the 
reverse need not follow. Thus, the generally higher hydrogen ion acidity 
of a tissue or of a fluid coming from that tissue is evidence of an increased 
acid content in the tissue, but considerable quantities of either acid (or 
alkali) may be introduced into any of our tissues, thereby raising their " acid 
content " even to the point of killing them, without any appreciable increase 
in the hydrogen ion acidity. When we add acid to a protein in the presence 
of an indicator the " acid content " of the protein rises from the moment 
we begin adding acid, but a long time may elapse and much may be added 
before the hydrogen ion acidity changes, as evidenced by a change in the 
color of the indicator. Would Henderson and his school hold that because 
the indicator had not turned no acid had yet been added? 

Beyond this the findings of Henderson and his co-workers do nothing 
but corroborate my own teachings. While in his first communication 
Henderson thought his results to dispose of my views entirely, his more 
recent conclusions are less sweeping. Thus, he finds " The mean acidity 
in cardio-renal cases is undoubtedly high . . . which other observations 
lead us to consider a form of acidosis" (Jour. Biol. Chem., 13, 404 (1913)). 
" This lack of response to alkali occurred most frequently in patients with 
kidney disease" (Arch. Int. Med., 12, 163 (1913)). "The hydrogen ion 
concentration from individuals with severe cardiac decompensation is 
higher than normal " and " the hydrogen ion acidity follows the general 
clinical course, becoming normal when compensation is restored " (Arch. 
Int. Med., 12, 146 (1913)). These conclusions sound strangely like my 
own. In the former of these articles Henderson advises against unchecked 
use of alkali in treatment because in too high concentrations it leads to 
albuminuria. This is a fact I emphasized long ago, but why is Henderson 
so willing to concede the albuminuria to be due to excessive alkali when he 



770 



(EDEMA AND NEPHRITIS 



Of the methods that have been or may be used to measure 
the hydrogen ion acidity of the urine (or any other .body fluid) 
nearly all are too complicated for routine clinical use. Those of 
S. P. L. Sorexsox and of L.J. Henderson are among the simplest, 

strains so over the analogous behavior of acid? Of course, Xewburgh, 
Palmer and Henderson found that " it could not be shown that there wa3 
any definite relation between hydrogen ion concentration of the urine and 
oedema in the cases studied" (Arch. Int. Med., 12, 146 (1913)). But then, 
as pointed out above, we learned in the late nineties that physiological 
effect is nowhere proportional to the hydrogen ion concentration. 

So far as the general biological views of Henderson are concerned he 
errs in these, as do most of the physical chemists working in biology. While 
I doubt not that the maintenance of neutrality in the organism is in good 
measure dependent on a play between monobasic and dibasic salts, some 
caution is necessary before all the conclusions of the physical chemists obtained 
on dilute aqueous solutions are bodily heaped upon protoplasm. Protoplasm 
is not a sack of water with a few salts dissolved in it. The water of pro- 
toplasm is hydration water and the dissolved substances are by no means 
all in simple solution. Not until it is shown that reactions occurring in 
gels are identical with those occurring in pure water — which we already 
know is not the case, for, as Findlat and Creighton ^Biochem. Jour., 5, 
294 (1911)) have shown, so simple a phenomenon as the solubility of oxygen 
in serum is only one-fifth as great as that in water — can we continue to apply 
without modification to protoplasm the physico-chemical laws governing 
reactions in dilute watery solutions. 

The latest criticisms of Henderson, Palmer and Xewburgh (Jour. 
Pharm. and Exp. Therap., 5, 449 (1914) ), upon which the Journal of the 
American Medical Association lays great stress editorially fJour. Am. Med. 
Assoc., 62, 2033 (1914 j, are equally inconclusive. Must it be reiterated that 
all salts, and particularly the phosphates and acetates used by Henderson, 
Palmer and Xewburgh as they were used by Max Koppel (Deut. Arch. f. 
klin. Med., 112, 594 (1913) ) even earlier — decrease and may suppress com- 
pletely the swelling of proteins no matter what hydrogen ion concentration 
surrounds them? Since gelatin and fibrin show increased swelling even in 
the lowest concentrations of carbonic acid it is not true that " no influence 
to increase colloid swelling has ever been observed through the action of 
hydrogen ions varying within the ranges of acidity known to occur in the 
body or in the urine." Further, it has never been maintained that labora- 
tory gelatin or fibrin was at once to be made identical with the proteins 
in our body. The body proteins are far more sensitive to acids, alkalies 
and salts than the long-suffering and mutilated materials we have salted 
and boiled out of them. The variations in the " acidity " of the blood noted 
by these authors are incorrectly maintained by them to be of no significance, 
for the fact remains that such as accompany mere change from arterial 
to venous blood already make the corpuscles hold 15 per cent more water, 
and if there is a passive congestion, 30. The clinician bases a diagnosis of 
oedema on a much smaller increase in general body weight than this. The 
arguments on the significance of " osmotic pressure " in water absorption 
by protoplasm may be referred back to the biologists who gave up the kind 
restated by Henderson, Palmer and Xewburgh ten and twenty years 
ago. 



NEPHRITIS 



771 



but even these require more time and skill than is always available. 
A series of phosphate or acetate mixtures having a known hydro- 
gen . ion acidity are first prepared to which indicators (dyes) 
are then added. The urines properly diluted and containing the 
same indicators are then matched against the colors in the stand- 
ard mixtures. The method has yielded valuable figures, but 
it is too complicated to find universal employment, and the 
degree of accuracy attained is, after all, not necessary for good 
judgment in medical practice. 

To get a method which would yield for clinical purposes suf- 
ficiently accurate data and still be simple enough to be employed 
by anyone, I have made use of graded indicators such as the 
physical chemists use. 1 By using a number of dyes which show 
color changes at definite hydrogen ion concentrations and then 
using the same indicators on the urine it is possible to determine 
its hydrogen ion acidity. The indicators are so chosen that 
their turning points vary from each other approximately by the 





Concentration of 


Color of indicator. 


Name of indicator and method 


hydrogen ions 






of preparing same. 


when indicator 








changes color. 


In acid 


In alkaline 






solution. 


solution. 


Methyl orange (0.5 gram in 100 cc. 










io- 4 


Salmon pink 


Orange-yellow 


Paranitrophenol (2 grams in 100 cc. 










10- 5 


Colorless 


Greenish-yellow 


Sive's red 1 (2 grams in 100 cc. 










IO" 5 tO -6 


Red 


Canary yellow 


Methyl red (0.2 gram in 100 cc. 










io- 6 


Magenta red 


Canary yellow 


Rosolic acid (0.5 gram, in 50 cc. 










10 - 7 - 


Orange-yellow 


Magenta 


Phenolphthalein (1 gram in 100 cc. 










io- 9 


Colorless 


Bluish-red 


Thymolphthalein (0.5 gram in 100 










io- 11 


Colorless 


Blue 



1 This is the hydrochlorid of paramonomethylaminoazobenzeneorthocarbonic acid. It 
does not turn until a hydrogen ion acidity higher than that necesary to turn methyl red 
is attained, and yet shows an acid reaction before such is discoverable with paranitro- 
phenol. Under the direction of Lauder W. Jones, B. Sive worked this out to meet the 
need for an indicator lying between these points. 



1 See Arthur A. Notes: Jour. Am. Chem. Soc, 32, 815 (1910), where 
is given an excellent discussion of the whole question of measurement of 
hydrogen ion aridity. See also Eduard Salm: Zeitschr. f. physik. Chem., 
57, 471 (1907). Fritz Glaser: Indikatoren, Wiesbaden (19U1); S. P. L. 
Sorensen: Biochem. Zeitschr., 21, 131 (1909); L. J. Henderson: Biochem. 
Zeitschr., 24, 40 (1910); W. M. Clark: Determination of Hydrogen Ions, 
Baltimore (1920). 



772 



(EDEMA AND NEPHRITIS 



power of ten. Of the many indicators which might be used 
those are best which do not give colloid precipitates when added 
to urine. The preceding series (see table on page 771), the end 
points of which are sharp and can be readily recognized even in 
highly colored urine, have given excellent results in my hands. 

In practice 10 cc. of urine are placed in a clean vessel (pref- 
erably a porcelain dish, which if distilled water is not available 
is first rinsed in the urine to be tested) and two drops of one 
of the indicators is then added to it. By trying successive 
indicators one is finally found toward which the urine is neutral. 
The urine has then the hydrogen ion concentration represented 
by the turning point of that indicator. As the acidity of the 
urine runs up, it will, of course, show an acid reaction to the 
upper members of the list, and as it runs down, to the lower. 
The turning point of the commonly used litmus is about that 
of rosolic acid. Urine not acid to phenolphthalein is alkaline to 
litmus, while thymolphthalein still remains colorless in urines 
which are distinctly alkaline to litmus. 

As is to be expected, the hydrogen ion acidity of the urine 
shows great variations even in health. A man doing muscular 
work, or on a predominantly meat diet shows a higher acidity 
than one in bed or on a predominantly vegetable diet. The 
urine after meals is less acid than that before meals, and the 
night and early morning urines are more highly acid than those 
obtained after breakfast. The measurement of the hydrogen 
ion acidity of the urine is one of the few tests in which averages 
and twenty-four samples give us least information, and one 
less valuable than isolated tests at frequent intervals. The 
reasons for this are obvious. An athlete starting with a urine 
alkaline to methyl red secretes one highly acid to this shortly 
after going to work. But the urine returns to the originally 
alkaline state after a short rest. In the period of observation 
the urine originally free of albumin and casts becomes rich 
in these and loses them again. Had we measured only the 
average acidity as obtained by mixing the three samples of urine 
we should never have discovered the acid wave and perhaps 
maintained that the hydrogen ion acidity never went above the 
normal, as do some of my critics. The same is true of the 
alleged " physiological " and orthostatic albuminurias. At bed 
rest the urine shows a degree of hydrogen ion acidity which 



NEPHRITIS 



773 



increases as the patient assumes the erect position (while albumin, 
casts, etc., appear at the same time) to fall again on resumption 
of the horizontal. Only many tests at frequent intervals will 
betray these constant changes. 

What we are interested in particularly, therefore, are the 
highest acidities registered and the length of time these remain 
active. Other things being equal, it is these two factors which 
determine how much effect is going to be produced on the 
colloids of the kidney. 

In practice, now, when will we say that our patient is not 
exceeding a safe hydrogen ion acidity of the urine? To get at 
this value I chose the highest hydrogen ion acidity registered 
by healthy men on a full diet , at bed rest. Such individuals do 
not* show a hydrogen ion acidity sufficient to turn methyl red to 
the acid side except, perhaps, in the night urines voided between 
two and seven in the morning. The urine of healthy individuals 
who are up and about and on a full diet is also alkaline to methyl 
red for most of each twenty-four hours, though for obvious 
reasons, muscular exercise, high meat and fat diets, etc., may 
increase these hydrogen ion acidities. 

In actual practice, therefore, methyl red should be used as 
the routine indicator for all urines. Those which have an acidity 
for the major portion of each twenty-four hours, or always, 
above this point I consider abnormally acid. Figures below 
this point and down to the turning-point of litmus or phenol- 
phthalein I consider normal. Phenolphthalein rarely shows 
an alkaline reaction (if ammoniacal decomposition of the urine 
is not present) unless alkali is being fed to the patient. When 
the urine becomes alkaline to thymolphthalein too large quan- 
tities of alkali are being given, and the possibility of getting 
an albuminuria due to alkali is at hand. 

When methyl red is used in routine fashion on all patients 
it will be observed that a large number run constantly acid to 
this indicator. This serves to bring home how common are low- 
grade types of acid intoxication. The more acute and the 
protracted infections, starvation cases, diabetics, patients with 
cardiac and respiratory disease, and patients with generalized 
parenchymatous nephritis all show an abnormally high hydrogen 
ion acidity. In ambulatory patients with chronic interstitial 
nephritis secondary to vascular disease such an abnormal 



774 



(EDEMA AND NEPHRITIS 



acidity may, for obvious reasons, be lacking, even though casts 
and albumin be present in the urine. In the later stages of 
the disease, especially when the circulation is beginning to fail, 
a high hydrogen ion acidity is the rule. When the acidity of 
the urine lies constantly below the turning-point of methyl red, 
or when by the administration of alkali it can be made to do 
so and be kept there, it augurs well for the patient. On the 
other hand, / cannot recall a single patient in whom it was difficult 
or impossible to hold the urinary acidity below that of the turning 
point of methyl red who did not die. 

The correlation between increase in the hydrogen ion acidity 
of the urine and the appearance of albumin and casts in it can 
be easity observed in athletes who voluntarily produce much 
acid, as well as in patients with orthostatic albuminuria, or in 
heart cases showing the first evidences of insufficiency. After 
exercise or on assumption of the erect position the acidity 
mounts from somewhere below the turning-point of methyl 
red to a place above, and if this is maintained for a little time 
casts and albumin are likely to appear. The more definitely 
neutral the urine before such added efforts, the longer does it 
take for the casts and albumin to appear. 

If the facts outlined are borne in mind the simple methods 
of measuring the hydrogen ion acidity described here prove 
of much clinical use. They apprise us of the existence of 
low degrees of acid intoxication in patients in whom we do 
not ordinarily consider them. By recognizing and meeting them 
by dietary regulations and alkali, we increase the reserve of 
these patients against the effects of such further intoxication 
as may be due to infection, anesthesia, or the trauma of opera- 
tion. Or, in the established case, a fall in the hydrogen ion 
acidity of the urine tells us that our therapy so far as alkalinizing 
the patient is concerned is of a successful type. Since the 
indicator method is exceedingly simple we can follow the patient's 
condition from hour to hour, an important fact when we deal 
with the acuter manifestations of nephritis and allied conditions. 
In cases of complete suppression, in other words, when there is 
no urine to tell us when we have succeeded in getting an adequate 
amount of alkali into our patient the reaction of the saliva serves 
as a useful guide. Ordinarily this is neutral to litmus paper, 
but it turns acid in various intoxications. Alkali should be 



NEPHRITIS 



775 



given until it again turns neutral or even slightly alkaline to this 
indicator. 1 

4. Limitations of Indicator Methods 

Recent studies on the colloid chemistry of soaps and proteins 
and the behavior of such systems toward various indicators 2 
serve to show the origin of the many erroneous deductions which 
have been made during the past years as the outgrowth of findings 
derived from the application of indicator methods to living cells 
and their secretions. Some remarks covering this matter, since 
they bear upon the questions discussed in this volume, are therefore 
necessary. 

Since the tissues, including the blood and lymph, are colloid 
systems and since the water in them is held as hydration water, I 
have insisted for many years past that ordinary physico-chemical 
laws and methods as derived from study of the ordinary " dilute" 
solutions cannot be applied to them without due reserve. I 
learned this more than a decade ago when, to prove the increased 
acid content of the tissues in oedema and nephritis, I tried to 
determine the hydrogen ion acidity of the blood. While in the 
more extreme cases such an increased acid content readily reveals 
itself by an increased hydrogen ion acidity, lower and known 
grades of acid intoxication produced by experimental means 
frequently fail thus to declare themselves to indicator methods. 
This is especially true when working (as one should) with undi- 
luted blood or blood plasma. The reason for this is now to be 
made plain. 

When a "neutral" hydrophilic colloid like soap or body protein 
(produced in the former case by adding to a standard amount of fatty 
acid the chemically necessary equivalent of standard alkali, or, in 
the latter instance by adding to each other the necessary gram equiva- 
lents of amino (fatty) acid and alkali) the resultant mixture is either 
acid, neutral or alkaline to such an indicator as phenolphthalein, 
depending upon the concentration of the water in the system. For 

1 The ordinary litmus paper is well-nigh worthless. It should always be 
tested for its sensitiveness before dependence is placed upon it. Only the 
neutral litmus paper of reliable manufacturers has proved of service in my 
hands. 

2 Martin H. Fischer: Science, 49, 615 (1919); Chem. Engineer, 27, 271 
(1919); see also Soaps and Proteins, New York (1920). 



776 



(EDEMA AND NEPHRITIS 



purposes of illustration may be chosen the behavior of a rather 
concentrated (molar) "solution" of sodium caseinate, potassium 
oleate or sodium oleate. Phenolphthalein added to such systems 
remains colorless as shown in the lower portions of the test tubes 
of Fig. 216. As soon, however, as water is added to these colorless 
mixtures all turn pink, and with increasing dilution, bright red. 




Figure 216. 



What has been said of these sodium soaps and sodium caseinate 
is true, in general, of all the soaps and all the proteins, though the 
more striking behavior is shown by the soaps of the higher fatty 
acids or the basic compounds of the more complex proteins. An 
indicator (like phenolphthalein) added to a chemically neutral 
sodium palmitate or sodium stearate-water system (either a solid 
gel or a liquid mixture) turns the liquid portion of the system a 
bright red while the masses of soap (or other colloid) floating in 
this liquid remain pure white. 

The common explanation of what happens in these instances is, 
of course, that of the physical chemists who assume that in the 



NEPHRITIS 



777 



concentrated soap " solution" there is little hydrolysis of the soap 
while in the more dilute one such hydrolysis is increased, and, 
sodium hydroxid being a stronger alkali than oleic acid is an acid, 
an indicator at once betrays the excess of hydroxyl ions. 

Without listing the objections which may be 'raised against 
such an explanation (which at best accounts for but a small por- 
tion of what happens) it seems necessary to us, in order to get a more 
satisfactory interpretation of the whole picture, to call to mind the 
physical constitution of the lyophilic colloids as previously dis- 
cussed in these pages, and, in the case of the soaps, to distin- 
guish between the behavior of those portions of such systems 
which have the composition water-dissolved-in-soap and those 
which have the composition soap-dissolved-in-water. The two 
are totally different and while indicator methods may be used 
in an attempt to analyze the latter, they need not be (and are 
not) so applicable to the former. The so-called concentrated soap 
"solutions" are essentially solutions of the solvent in the soap, 
the more dilute ones systems of the opposite type and physico- 
chemical methods and the laws governing dilute solutions may 
therefore be applied only to the latter. The indicators may help 
for those portions of the system which are of the composition x-dis- 
solved-in-water but they need tell us nothing of those portions 
composed of water-dissolved-in-x. 

The reactions in the solid tissues of the body (including for the 
most part those in the blood and lymph) are reactions in a medium 
analogous to a concentrated soap or protein-water system. The 
reactions, on the other hand, occurring in the watery secretions 
from the body (like the urine, saliva, gastric juice or sweat) are 
for the most part occurring in a system analogous to a diluted soap 
or protein. As the above facts have shown, indicator methods 
may be applied, with a fair degree of accuracy only to the last 
named of these systems and yet it is the common practice of 
biochemists, biologists and clinicians to assume that protoplasm, 
too, is something analogous to a dilute solution. 

The observations detailed above carry with them an interesting 
corollary. The color changes of indicators are in the majority of 
instances assumed to be dependent upon a play between the con- 
centration of the electrically charged hydrogen and hydroxyl 
ions. If this assumption is held true for phenolphthalein (or for 
any other indicator which is held to act in this fashion) and especi- 



778 



OEDEMA AND NEPHRITIS 



ally if anyone maintains that such indicator methods may be 
applied to concentrated lyophilic colloid systems, then the conclu- 
sion is inevitable that such concentrated systems contain no such 
ions. The matter is of significance because living matter (normal 
protoplasm) behaves not as is so widely assumed, as water con- 
taining a little colloid but, more correctly ; as a colloid containing 
some water. If this be true — and all experimental evidence 
supports such a conclusion — then the material which we call living 
matter is probably under normal circumstances as electrically bland 
as is a concentrated soap solution, a conclusion not to be overlooked 
in a day when the explanation of almost every fundamental life 
process is assumed to he in an electrical notion of some kind. 
This criticism is not to be misunderstood. Differences in electrical 
potential, in ionization, etc., do come about in living matter, 
but they are more probably the results and the expression of 
injury to the involved structure than characteristic of the normal 
life of such. 

It is well to emphasize also that only the normal cells are essen- 
tially systems of water-dissolved-in-protein. Indicators are there- 
fore trickiest when applied to these systems. In disease the 
affected cells suffer changes which often are in the direction of 
"true" solution, in other words, the cells tend to develop into 
systems of the type, protoplasm-dissolved-in-water. ' Indicator 
methods become more reliable as this happens but only for those 
portions of the cell which are of this "true" solution type. 

5. Ammonia Determinations, Acetone Compounds, "Acidosis," 

and Coma 

In addition to measuring the titration or hydrogen ion 
acidity of the urine there is available another scheme of analysis 
which gives light regarding the existence and degree of acid 
intoxication within the body. The living animal labors constantly 
to keep as low as possible and to render as innocuous as possible 
the acids steadily produced in its normal or abnormal metabolism. 
It does this whenever possible by converting the products of its 
metabolism into carbonic acid, which may be lost from the body 
through respiration without simultaneous loss of an equivalent 
amount of alkali. All non-volatile acids such as sulphuric or 
phosphoric can be lost (through one of the secretions, like the 
urine) only by dragging along a minimal equivalent of alkali. 



NEPHRITIS 



779 



In many metabolic disturbances there is an interference 
with the normal production of carbonic acid, and then other, 
largely non-volatile acids, are produced in its place. These can 
be eliminated only in the form of salts produced through union 
with the bases of the body. When such abnormal production 
or accumulation of acid is not too intense, the reserve of bases 
in the body is usually sufficient to meet the need and the whole 
derangement comes and goes without disastrous effects upon 
the organism. But let the process be continued and this is not 
the case. In the herbivora the animal survives acid intoxica- 
tion until its fixed alkali (the metallic bases) has been exhausted 
down to the physiological minimum. But in the carnivora 
(with which man is to be reckoned) a second source of base is 
available which, if it exists in the herbivora, is negligible in 
amount. When the fixed bases of the carnivora are heavily 
drawn upon these animals begin to produce ammonia and to use 
it to neutralize the acid. The carnivora can therefore withstand 
a continuous acid intoxication longer than can the herbivora. 

In these simple considerations are embodied certain principles 
of analysis which have not yet found their deserved place in the 
practical handling of the nephritic. While they have long been 
used to advantage in diabetes and other metabolic disturbances 
they have been largely discarded in nephritis. The error of so 
doing will become apparent as we proceed. 

Clearly, when an individual for any of a number of reasons 
becomes the subject of an intoxication with acid this may 
betray itself in the fluids coming from his body, as in the urine 
(feces, sweat, or saliva), not only by an increased titration or 
hydrogen ion acidity, but in either or both of the following 
two ways: 

(a) By the appearance in it of acids which do not normally 
occur there, or 

(6) By a relative or absolute increase in the amount of 
ammonia given off. 

Many of the now available tests for the presence of diacetic 
and betaoxybutyric acids in the urine as well as for the related 
acetone can be quickly performed and are so simple as to be 
within the reach of the busiest practitioner. 1 The recogni- 

1 An excellent small guide thereto is S. W. Cole's Practical Physiological 
Chemistry, Cambridge (1913). See also Martin H. Fischer: Tice's Practice 
of Medicine, 1, 423 (1920). 



780 



(EDEMA AND NEPHRITIS 



tion of lactic acid is also* easy. As none of these or similar 
substances are found in appreciable amounts in normal urine 
their mere qualitative recognition becomes evidence for an 
abnormal body chemistry. But it means no more than this. 
One is not immediately to conclude that an " acidosis" 1 exists, 
if by this term is meant an intoxication with acid. An acetone 
body, lactic acid or any other normal or abnormal acid may be 
produced in great quantities in the organism and appear in the 
urine, yet if sufficient base is available they are neutralized and 
so are practically without effect. Even good men seem to for- 
get this constantly. On the other hand, no acids of abnormal 
kind need be present in the urine (or elsewhere) and, yet the organ- 
ism be suffering from an intense degree of acid intoxication (as with 
phosphoric or sulphuric acids) if the available supply of base has 
been exhausted. 

Since the normal amount of ammonia in the urine of an 
animal (like man) does not exceed a certain value, and since 
ammonia is not used to neutralize acid until the available fixed 
bases have first been heavily drawn upon, an absolute increase 
above the normal of the amount of ammonia in the urine 
becomes evidence of an acid intoxication. Furthermore, since 
the ammonia is formed at the expense of some of the other 
products of protein metabolism which escape in the urine, 
a relative increase in -the amount of ammonia as compared 
with the total urea (or total nitrogen) of the urine is observed 
whenever an acid intoxication is under way, and becomes 
evidence for such. 

As comparatively simple methods are now available for the 
quantitative estimation of ammonia and of urea (or total nitrogen) 
in the urine they are sure to find renewed application to many 
patients in whom an acid intoxication followed by nephritis 
is feared or existent. The considerations which led the older 
observers to discard such analyses as valueless depended 

1 The word "acidosis" has had its meaning twisted so greatly to suit 
the whims of different authors that it might well disappear from our medical 
and physiological writings. If it 4s used at all it must be used in its original 
sense as synonymous with "intoxication with acid." The mere finding 
of various abnormal acids or "acidosis compounds" in the urine or else- 
where does not yet mean an acid intoxication. The acetone bodies of a 
diabetic do not betray an acid intoxication, but an altered chemistry from 
which an acid intoxication may result, 



NEPHRITIS 



781 



upon the wrong interpretations which they made of their 
findings. 

As is well known, routine examination of the urine of all 
patients reveals the fact that acetone, diacetic acid, betaoxy- 
butyric acid, etc., occur in a large number of different clinical 
entities. Not only are they found in diabetes, but they occur 
in all types of general starvation, carbohydrate starvation, in 
many of the fevers (frequently in consequence of the bad feeding 
incident thereto), in cyclic vomiting, in certain of the so-called 
autointoxications, etc. Lactic acid, on the other hand, is 
found in uncompensated heart lesions, in severe anemias, in 
severe respiratory disease, in various intoxications, and in other 
conditions in which a lack of oxygen in some or all of the tissues 
of the body is in evidence. The finding of any or all of these 
abnormal constituents in the urine is .evidence of an abnormal 
chemistry which may be followed by the signs and symptoms 
of a nephritis. Recognition of them in the urine is therefore a 
warning that the signs of a nephritis may supervene if care is 
not taken to feed properly (carbohydrate feeding) or to see that 
an adequate amount of alkali gets into the body to neutralize 
the acids. In the established nephritis the disappearance of 
these substances from the urine indicates that our therapy has 
been of an adequate and successful kind, a conclusion often 
brilliantly confirmed by the rapid disappearance of albumin and 
casts from the urine and of cedema from the body generally. I 
re-emphasize the necessity of keeping in mind that even large 
quantities of these abnormal substances may be found in the 
urine without any signs of nephritis, and conversely, that a 
severe nephritis may show but little of these substances or none 
at all. Thus, in diabetes large quantities of the acetone bodies 
may be found without the signs and symptoms of a nephritis, 
as long as an adequate amount of alkali is present to neutralize 
them. When the alkali becomes deficient the diabetic begins 
to show casts and albumin in the urine, to retain water (develop 
an cedema) and to have his brain affected in this general process 
(brain cedema and coma). Some of my critics seem constantly 
to forget these facts, as also that 40 per cent of all diabetics, 
especially those in the latter stages of the severer types of the 
disease, show casts and albumin. 

What has been said of the diabetic (who really represents in 



782 



(EDEMA AND NEPHRITIS 



essence but a severe grade of carbohydrate starvation) is true, 
of course, of all who suffer from carbohydrate starvation from 
any cause whatsoever, as in cyclic vomiting, in the protracted 
fevers, in the starvations associated with gastric ulcer, malignant 
tumors, tuberculosis, etc. To judge properly of the actual 
degree of acid intoxication from which such patients are suf- 
fering we cannot rely solel} r upon the discovery of abnormal 
urinary constituents. A better index, as we have already 
emphasized, is found in the measurement of the titration and 
hydrogen ion acidities of the urine. To this we may add the 
quantitative estimation of ammonia in the urine and the deter- 
mination of the ammonia coefficient. 

For oft -emphasized reasons the ambulatory case of chronic 
interstitial nephritis associated with vascular disease need show 
no abnormal total ammonia excretion or abnormal ammonia 
coefficient (total ammonia divided by total urea or total nitro- 
gen) 1 The dying spots of (parenchymatous) nephritis in the 
kidney need not produce enough acid to affect the mixed urine 
coming from the whole kidney. Such a patient has large amounts 
of normal kidney substance left, and as long as his heart and 
circulatory apparatus is not too heavily taxed he does not 
develop acid in sufficient amounts to call into play this ultimate 
neutralization mechanism of ammonia production. In fact, 
such a patient may die in coma (so-called " uremia ") and 
yet show no increased ammonia output. This coma is, to my 
mind, an oedema of the brain, but since it is usually secondary 
to vascular disease the acid production is largely local and 
there is no reason why the body as a whole should show evi- 
dence of a general acid intoxication, to betray itself through 
an abnormal ammonia output in the urine. If the coma persists 
and the patient is not fed, or if convulsions supervene, the 
ammonia output is regularly found to rise. Because of this rise 
in ammonia output in the course of the coma it has been 
reasoned that the original " uremia " caused it and that the 
" uremia " itself cannot have been an acid intoxication of the 
brain (oedema of the brain). If what has just been said be 
borne in mind, it becomes readily intelligible how in the begin- 
ning there was an oedema of the brain (due to local acid intoxica- 

1 The figure obtained is practically the same, as normally, urea con- 
stitutes over 90 per cent of the total nitrogen. 



NEPHRITIS 



783 



tion) and how through this with its attendant bad feeding, 
etc., the patient's condition was made steadily worse. 

An increased total and relative ammonia output is, as we 
should expect, particularly common in the so-called generalized 
parenchymatous types of nephritis, especially when protracted 
as in those incident to pregnancy. As a rule, these cases show 
with increase in albumin, casts, etc., or with increase in the gen- 
eralized oedema, or with increase in the severity of the symptoms 
premonitory of coma and convulsions, an increase in either the 
total or the relative ammonia output. Where normally the 
ammonia coefficient does not exceed 5 or 6 per cent of the total 
urea or nitrogen (or in absolute amounts, 0.3 to 0.6 gram a day) 
such cases will show 10 per cent of ammonia or even more (with 
an absolute output of 2, 3 or even 4 grams a day) . 

These considerations suffice to indicate how important it is 
to follow the absolute and relative ammonia excretion in any case 
in which a nephritis is feared or existent. The value of such 
determinations in diabetes by way of foreseeing and forestalling 
coma has long been recognized. The coma incident to neph- 
ritis, like the coma of diabetes, is an oedema of the brain, and its 
appearance, particularly in the so-called generalized parenchy- 
matous types of nephritis, can be foretold with the same degree 
of assurance. 

A long series of observations on the absolute and relative 
amounts of ammonia found in the urine in cases of nephritis 
are available. What has been lacking is their proper interpreta- 
tion. Rudolph von Jaksch, finding the ammonia output 
high in a number of nephritics, declared the nephritides to 
represent a type of acid intoxication. It is a view with which 
I heartily concur in spite of the many criticisms of it that have 
appeared since von Jaksch's original communication. 

XIII 

PROPHYLACTIC MEASURES AGAINST NEPHRITIS. CARE 
OF THE SURGICAL AND MEDICAL PATIENT 

It becomes apparent from what we have said above that 
the mere diagnosis of nephritis has little meaning. It is as com- 
plete as a diagnosis of "dropsy," "fever" or "headache." We 
found the nephritides to divide themselves into three groups — 



784 



(EDEMA AND NEPHRITIS 



into a toxic type in which a poison from some source affects the 
kidney, an infectious type again essentially toxic in nature but 
harboring organisms in the kidney itself, and a vascular type 
in which destructive lesions are consequent upon involvement 
of the blood vessels of the kidney by vascular disease. The 
first of these necessitates search for the source of the toxic agent; 
the second for the source and type of the infection in the kidney; 
the third for foci of infection responsible for the primary changes 
in the blood vessels. The infections of the kidney and vascular 
disease of the kidney come to us, at present, largely ready made, 
and so in these patients we must content ourselves with stopping, 
if possible, the progress of their pathological states and counter- 
acting as well as we may their effects upon the kidney. We 
can do most from a prophylactic standpoint for the toxic nephri- 
tides. Evidently, if alkali, salt, carbohydrate and water relieve 
the signs and symptoms of the established toxic nephritis (and 
of the toxic portion that may be present in the other nephri- 
tides) the same measures will largely suppress or prevent their 
development if used prophylactically. It is more spectacular, 
by the. use of alkali and salt to save a woman in convulsions, 
say from a pregnancy intoxication, but it is better medicine to 
instruct her in the methods of preventing such a condition alto- 
gether. And what is true of a pregnancy is true of any other 
established or anticipated type of intoxication in which dis- 
turbances from the side of the kidney are feared. 

Our surgical and medical wards are filled with patients about 
to be operated upon or ill of various maladies in whom we can 
do much to lessen or shut out entirely such possibilities. 

§ 1 

An interesting and easily manageable group is furnished by 
the surgical patients. Much of their ante-operative preparation 
used to be and, in some places still is, of a type to guarantee 
from the outset a maximum of discomfort and even danger to 
the patient. Routine examination of the urine of patients about 
to be operated upon, even when not suffering from infections 
or intoxications likely to be complicated by nephritis, shows that 
in the days before their operations they are usually pushed into 
a state in which post-operative complications are very likely to 



NEHPRITIS 



785 



appear. 1 Commonly, the urine shows even before operation 
a high hydrogen ion acidity (acid to methyl red or even para- 
nitrophenol) . Such patients make poor surgical risks, and 
should be given the benefit of preliminary treatment. The 
mental anxiety so common in the surgical case expresses itself 
physiologically by increased muscular tone, and this declares 
itself chemically by a great acid production which mirrors itself 
in the high acid findings in the urine. How much the intelligent 
reassurance of the surgeon must mean to such a patient is obvious. 

Patients are also thoughtlessly ordered upon a " light diet." 
In this way the acid products of a starvation diet are added to 
those already present from other sources. Unless there are 
specific reasons against it, a surgical 'patient should be fed to 
within a few hours {about six) of his operation, and since carbo- 
hydrate starvation is the commonest and earliest form, special 
attention should be paid to getting an adequate sugar-starch 
ration into him in any form he may desire (potatoes, mush, 
toast, bread, sugar, candy). 

In addition the patient should be fed alkali in some agreeable 
form. Any scheme for accomplishing this is good, but the use 
in large quantities of artificial or natural alkaline waters is 
perhaps simplest and best. If conveniently possible the alkali 
should be used for several days before the operation and up to 
the point where the patient has a persistently neutral or somewhat 
alkaline urine. A patient that goes upon the operating table 
with highly acid urine, or with a high ammonia coefficient, 
or shows qualitative disturbances in his metabolism as evidenced 
by acetone, diacetic and betaoxybutric acid in the urine, is 
in this proportion a bad surgical risk. An apparently poor 
risk, free from such findings, is almost certain to withstand 
anesthetic, the necessary trauma of operative interference, etc., 
without difficulty. 

James J. Hogan, Hayward G. Thomas, Gordon F. McKim, 
Charles A. Pauson and William Mithoefer have long prepared 
their surgical patients in this manner, and find that they do better 
than on the old expectant scheme. The patients recover more 
rapidly from the effects of their anesthesia, they are without 
headache (absence of brain oedema) they vomit little or not at all 

1 For a report of fatalities due to "acidosis" in surgical patients see 
W. B. Russ: Jour. Am. Med. Assoc., 61, 1618 (1913). 



786 



(EDEMA AND NEPHRITIS 



(absence of oedema of the medulla), they urinate an hour or two 
after the operation (absence of kidney cedema and early presence 
of "free" water), and the urine is practically free from the 
acetone, diacetic acid, albumin and casts so common post- 
anesthetically. Moreover, the traumatized tissues at the seat of 
the operation swell less and are less painful (less cedema). 

McKim, for example, found that in a series of eighty sur- 
gical operations on the prostate, treated on the old expectant 
plan, he encountered much post-operative nausea, vomiting and 
gaseous distention of the bowel and some evidences of shock. 
Two patients became maniacal after the operations. Of a second 
series of fifty cases, in which nothing in operative technic or 
general hospital care was changed except that the patients were 
fed to within a few hours of operation and were given sodium 
bicarbonate and magnesium oxid, with much water until the 
urine was persistently neutral to litmus, he writes: "There 
has not been a single case of post-operative vomiting, practically 
no gas distention, and not one case of shock. The excellent 
condition of patients so handled is not to be compared with that 
of such not previously alkalinized. They are in better spirits 
mentally, in less pain and heal more quickly. This sounds 
strange, but my last cases have healed more quickly by a week." 

The toxic effects of an anesthesia so far as the kidneys are 
concerned deserve consideration from several viewpoints. In 
the first place, no anesthetic, be this chloroform, ether or nitrous 
oxid, can produce its desired effects without interfering with 
the oxidation chemistry of the body. In fact, anesthesia depends 
largely, if not entirely, upon such an effect. We need not, 
however, add to this load by giving the patient too little oxygen. 
One of the superior merits of nitrous oxid-oxygen anesthesia resides 
in the fact that oxygen accompanies it. The other advantage is 
that profound anesthesia may be obtained quickly and be gotten 
over quickly — the nitrous oxid is, in other words, highly volatile. 
There is absent in consequence what might be termed the post- 
anesthetic or post-operative anesthesia of several hours' duration 
always incident to chloroform, ether and similar anesthetics. 

It should also be remembered that the bad effects of an anes- 
thesia are not simply a function of its length and the quantity 
of anesthetic used. Alvin Powell 1 found in a carefully studied 
1 Alvin Powell: Personal communication (1913). 



NEPHRITIS 



787 



series of operation cases that patients in whom but little 
anesthetic was used (and in whom perfect muscular relax- 
ation was not obtained) showed more casts, albumin, etc., in 
the urine than those anesthetized longer and more deeply. On 
the other hand, very deep anesthesia was again followed by 
more albumin and casts. These facts are to be interpreted as 
follows: The bad toxic effects avoided by use of but little 
anesthetic are more than counterbalanced by those incident to 
the great acid production consequent upon imperfect muscular 
relaxation. The imperfectly anesthetized subject responds with 
muscular contraction to the irritation due to surgical trauma. 
Surgeons seem constantly to forget that even when such rela- 
tively "deep" reflexes are no longer apparent still deeper ones 
which happen not to show themselves in external movement 
are still being elicited. A medium degree of anesthesia increases 
the toxic factor of the anesthetic but eliminates the acid factor 
due to muscular rigidity. In deep sleep a maximum of inter- 
ference with normal oxidation chemistry is again assured by the 
anesthetic itself. 

Similar considerations hold in determining the value of 
morphin, atropin, scopolamin, and similarly acting drugs admin- 
istered before or after an operation. In my own opinion atropin 
and scopolamin might well be eliminated. Atropin is valueless 
as a cardiac "'stimulant" and is one of the worst of drugs in its 
ability to interfere with the normal oxidation chemistry of cells, 
while scopolamin acts as a cerebral excitant quite as often as a 
depressant. I have never, in surgical patients, seen atropin do 
good, while I am confident that it was responsible for several 
accidents (glaucoma, cardiac insufficiency, "shock," acute urinary 
suppression). Suprarenal derivatives should also be used carefully. 
While they guarantee a dry operating field, they as surely guaran- 
tee a bleeding field later. As E. C. van Leersum 1 has shown, in 
irreproachable experiments, the vasoconstrictor and blood-pressure- 
raising effects of epinephrin last only a few minutes to be followed 
by a vasodilatation and drop in blood pressure to far below the 
normal which lasts days. Morphin or morphin derivatives there- 
fore remain alone to be considered. With a good anesthetist even 
their administration before an operation may be only a handicap. 
With a poor anesthetist, their bad effects may be offset by the 
1 E. C. van LEERStJM: Pfltiger's Arch., 1.42, 377 (1911). 



788 



(EDEMA AND NEPHRITIS 



assurance of better muscular relaxation and the elimination of 
acid production from this source. 

The use of narcotics after operations becomes a matter of 
balancing their bad effects in interfering with the oxidation chem- 
istry of the body against the good effects incident to elimination 
of the great muscular reaction, etc., consequent upon pain. The 
value of local anesthetic measures (cocain, novocain, etc.), as in 
nerve blocking and in tissue infiltrations, is similarly ex- 
plained. Their use prevents pain impulses from reflexly express- 
ing themselves in increased muscular tone, but it should be 
clearly borne in mind that their careless or immoderate use is 
not without bad effects. 1 

In the after-treatment of these surgical patients, a plentiful 
supply of air and an early reestablishment of a carbohydrate-rich 
diet with fruit juices, and alkaline drinks does much to hasten 
convalescence. The reasons for this are self-evident. Air not 
only means opportunity for the rapid elimination of the volatile 
anesthetics but the presence of much oxygen for the oxidation 
of lactic and other acids. As Fletcher and Hopkins have shown, 
a " fatigued" muscle — and the surgeon should remember that his 
worn out or mildly " shocked" surgical patient is suffering the 
same kind of chemical fatigue in all his voluntary and involuntary 
muscle — will oxidize a third of its content of lactic acid in a couple 
of hours and over half of it in six or seven. The patient recovering 
from an anesthetic needs food. His nausea — which is not likely 
to be present if properly treated beforehand — is of central origin, 
not peripheral. Withholding food from the stomach will not cure 
it while such starvation may actually make the central disturbance 
worse. To control the psychic factor in gastric secretion and 
motion the patient should be asked what he desires and then should 
be led to desire carbohydrates, as the ices, ice creams, fruit juices 
with much milk sugar, creamed toasts, milk with milk sugar, etc. 
The so necessary alkali may be given by mouth or rectum but 

1 1 cannot help but endorse here the excellent surgical methods urged by 
George W. Crile in the protection of his patients against shock, and this 
in spite of the fact that I am not of a mind with him regarding its nature 
and cause. I cannot escape the conviction that the central nervous system 
changes which he describes (swelling of cells with changes hi their staining 
properties) are not the causes but the consequences of shock and to be 
explained in the same way as the cedemas which characterize the swollen 
glandular and body tissues elsewhere in the organism. I shall return to 
this question in detail at another time. 



NEPHRITIS 



789 



enough must be administered — enough to keep the urine constantly 
neutral to litmus or alkaline to methyl red. Carbonated alkaline 
drinks may be used or baking soda enemas, three to four times in 
the first twenty-four hours and then twice daily — but always in 
sufficient numbers to accomplish neutralization. It is too often 
forgotten how much acid production follows the ordinary anes- 
thetic. Maurice Nicloux and G. Fourquier 1 calculate that 50 
per cent of the administered chloroform is broken into acid com- 
pounds and that for each gram thus broken a gram of sodium (or 
more of potassium) is needed to accomplish neutralization. When 
other anesthetics are used the same acid poisoning follows, the 
degree being determined by the amount and nature of the anes- 
thetic used. As Evarts Graham 2 has found, the poisonous 
effects of the anesthetics largely parallel the amounts of hydro- 
chloric acid which they yield on breakdown which explains why 
tetrachlormethane, chloroform, dichlormethane, ether and chloral 
hydrate are decreasingly poisonous in the order named. 

In much the same way that we have discussed the protection 
of a patient against the effects of an anesthesia intoxication we 
may also guard him against the consequences of other intoxica- 
tions. The effects of arsenic (salvarsan) offer a case in point. 
It may be only good fortune, but I think not, that I have never 
had a serious salvarsan complication and that none has occurred 
in the practice of my colleagues who before injection take the 
precaution of thoroughly alkalinizing their patients. The 
blindness (optic nerve cedema), headache (brain cedema), vomit- 
ing (medullary oedema), generalized oedema, decrease in urinary 
output with blood, casts and albumin (cedema of kidneys), 
pain in various sensory nerves, etc., which have been so fre- 
quently described, and which, when sufficiently severe, may end 
in death, are more easily interpreted as cedemas due to arsenic 
intoxication than as syphilitic manifestations fanned to fire 
by the arsenic injections. In consequence of syphilitic disease, 
tissues on the verge of oedema through connective tissue over- 
growth, defective blood supply, pressure, etc., are pushed over 
the line by the arsenic intoxication. Thorough alkalinization 
beforehand (and treatment with potassium iodid has much the 

1 Maukice Nicloux and G. Fourquier: Presse Medicale, 20, 729 (1912). 

2 Evart3 Graham: Jour. Exp. Med., 22, 48 (1915); Jour. Am. Med. 
Assoc., 69, 1666 (1917). 



790 



(EDEMA AND NEPHRITIS 



same effect) tends to prevent the disastrous consequences of such 
superimposed cedema. And let me add that I have used the 
salvarsan in the very cases in which it is ordinarily forbidden, 
namely in tabes, optic nerve and brain lesions, arteriosclerosis, 
aneurysm and kidney disease (so-called chronic interstitial, 
nephritis with high blood pressure) when I felt syphilis was a 
factor in the case. 

§ 2 

What has been said of surgical patients holds with equal force 
for many of the medical ones. Their routine examination reveals 
a great majority suffering from medium and at times high-grade 
states of acid intoxication. Analysis of the urine is our best guide 
to the discovery of such handicapped individuals, but the retention 
of water by the patient (as evidenced by weighing him), the slight 
general cedemas so frequently observed, the headache, the vomit- 
ing, the rapid pulse, the quickened respiration 1 and the appear- 
ance of albumin and casts in the urine all further betray the fact. 
The tests for low alveolar carbon dioxid tension and the measure- 
ments of the " alkali reserve" in the blood which have become 
popular during the past years are all expressive of the same 
fundamental acid intoxication. The amount of carbon dioxid in 
the expired air falls whenever any stronger acid appears in the 
blood and " blows off" the carbonic acid; while the "alkali reserve" 
must evidently fall whenever a draft has been made upon it by 
acid. 

The sources for the acid production are, of course, many. The 
various intoxications incident to the infections lead to great acid 
production. To this are often added the acid effects of inadequate 
feeding. The food may be badly chosen or be insufficient in 
amount, or in his illness the patient may not take enough. If he 
becomes mentally excited or develops a convulsion, say in the 

1 The patient suffering from an acid intoxication from any source what- 
soever cannot hold his breath as long as can a normal person. Yandell 
Henderson (Jour. Am. Med. Assoc., 63, 318 (1914)) with his customary- 
keenness has indicated how this fact may be used as a simple and accurate 
guide to the degree of acid intoxication clinically. A normal person after 
resting for five minutes and then ordered to take a full but not abnormally 
deep inspiration can hold this with closed mouth and nose for 30 to 40 
seconds. If partially poisoned with acids the breath cannot be held so long, 
a patient able to hold it only 20 seconds or less constituting a bad surgical 
prospect. 



NEPHRITIS 



791 



course of an infectious disease, then the products of such excessive 
muscular work are added, and his precarious state is further aug- 
mented. 

It must be self-evident how much we can do both to prevent 
and to relieve these conditions. It is not difficult in beginning 
cases to feed enough alkali by mouth to keep the urine persistently 
neutral. If such proves inadequate, enemas of sodium bicarbon- 
ate (12 to 18 grams to the liter) or of sodium carbonate and 
salt may be used. The necessity of sufficient carbohydrate 
feeding has long been emphasized by different authors. When 
the oral route is not adequate, rectal injections of dextrose (glu- 
cose) do much good. But it should be remembered that only 
dextrose is easily absorbed, and that the common practice of 
giving starch, milk, milk-sugar or cane sugar enemas and like 
concoctions is valueless, for these higher carbohydrates are 
scarcely absorbed. Moreover, several hundred (about 500) grams 
of carbohydrate are required per day — a fact which will suffice to 
emphasize the complete inadequacy of the teaspoonful methods 
of feeding so commonly encountered in practice. 

When both mouth and rectum are inadequate, good, and at 
times, startlingly good results are obtained by giving chemically 
pure dextrose intravenously. For reasons previously empha- 
sized, this is best given very slowly in concentrated form (45 
grams dextrose per 100 cc. of water). 

To the mind which never asks what is the nature of the 
processes that characterize disease and what is the purpose 
and the ultimately accomplishable in therapy, the attempts at 
analysis, and the suggestions for treatment outlined in these 
pages, can mean but little. What I have said has been variously 
commented upon. To Theodore C. Jane way my reports on 
the relief of patients, in whom objectively judging colleagues 
had felt only a fatal issue possible, "read like the cures of the 
nostrum venders." 1 To others the patients would have recov- 
ered anyway. Some believe the whole procedure valueless. 
Henderson, Palmer and Newburgh find it "harmful and 
productive of human suffering." 2 How proper use of alkali, 

Theodore C. Jane way: Unsigned review of first edition of my 
"Nephritis." Arch. Int. Med,, 9, 637 (1912). 

2 Henderson, Palmer and Newburgh: Jour. Pharm. and Exp. Therap., 
5, 466 (1914). The opinion is shared by Lawrence Litchfield: Jour. 



792 



(EDEMA AND NEPHRITIS 



salt and sugar can produce such strange results is incompre- 
hensible. Some hold what I have written as essentially true. 1 
In the dilemma I advise anew that the objective thinker in 
medicine reject my views and first treat his patient with nephri- 
tis and its alleged consequences by more approved methods. 
If he should feel that his patient is going to die, alkali, salt and 
sugar might be tried. If the patient dies, the expected will merely 
have happened. If he lives, it proves nothing, but it may encour- 
age repetition of the experiment. And this, I feel, is all that is 
necessary. 

Am. Med. Assoc., 63, 307 (1914). The value of Litchfield's evidence has 
been analyzed by Paul G. Woolley: Jour. Am. Med. Assoc., 63, 596 (1914). 
Similar criticism bv A. R. Moore: Univ. Calif. Pub. Physiol., 4, 111 (1912); 
Pflugers Arch., 147, 28 (1912); ibid., 148, 167 (1912); Jour. Am. Med. 
Assoc., 59, 423 (1912) and 60, 345 (1913), I have answered myself. Fischer: 
Jour. Am. Med. Assoc., 59, 1429 (1912); 60, 348 (1913). 

3 E. O. Smith: Lancet-Clinic, 107, 213 (1912); Arthur D. Dunn: Lancet- 
Clinic, 108, 8 (1912); Albert J. Bell: Am. Jour. Med. Sci., 144, 669 (1912); 
personal communication (1914); Magnus A. Tate: Bull. Acad. Med. Cin- 
cinnati, 1, No. 22 (1912); Lancet-Clinic (1912); Edgar G. Ballenger and 
Omar F. Elder: Jour. Am. Med. Assoc., 62, 197 (1914); Rufus South- 
worth: Lancet-Clinic, Sept. 5 (1914); Gordon F. McKtM, Personal com- 
munication (1914); H. Lowenburg: Jour. Am. Med. Assoc., 63, 1906 
(1914); James J. Hogax: California State Jour. Med., 13, 50 (1915); Lancet- 
Clinic, 113, 6 (1915); Jour. Am. Med. Assoc., 67, 1826 (1916); George J. 
Grinxan: Virginia Med. Semi-Month., 20, 523 (1916); H. B. Weiss: Jour. 
Am. Med. Assoc., 68, 1618 (1917); Ohio State Med. Jour., 13, 595 (1917); 
J. Michell Clarke: Brit. Med. Jour., 2, 239 (1917); Herbert Brown: 
Personal communication from Flanders, received Sept. 1, 1917; W. de B. 
Mac Nider; Jour. Exp. Med., 23, 171 (1916); ibid., 26, 19 (1917). 



PART SEVEN 
GLAUCOMA 



PART SEVEN 



GLAUCOMA 



I 

ON THE NATURE AND CAUSE OF GLAUCOMA 

From a pathological standpoint, glaucoma represents simply 
one of the local cedemas. From a clinical point of view, all its 
signs and symptoms have since von Graefe's teachings (1860) 
been correctly referred to the increased intraocular pressure 
induced through the abnormally large amount of water held 
by the eye. How does it come to do this? 

A glance at any of the standard works on ophthalmology 1 
shows no dearth of attempts to answer the question, but experi- 
ments planned to support the views advanced by the various 
authors have been singularly unsuccessful. For the most part, 
when not simply referred to the occult properties of " living " 
matter, these explanations are identical with those given for 
oedema anywhere else in the body. They are familiarly mechan- 
ical in character in that an increased lymphatic or blood pressure 
is supposed to force an abnormally large amount of liquid into 
the tissues of the eye. Such increased pressures are generally 
held to be induced through interference with the outflow of 
lymph or of blood from the eye occasioned through obliteration 
of the " filtration angle," etc. 

The experiments detailed in a previous section of this volume, 2 
and instituted in order to ground experimentally the colloid- 

1 See, for example, Ernst Fuchs: Augenheilkunde, Zwolfte Auflage, 
523; Leipzig u. Wien (1910); Priestly Smith: Glaucoma, London (1891). 

2 See page 169. 

795 



796 



(EDEMA AND NEPHRITIS 

i 



chemical conception of oedema, showed clearly that the most in- 
tense grades of glaucoma can be induced experimentally in an eye in 
the entire absence of any circulation. This fact coupled with the 
well-known observation that any experimental increase in the pres- 
sure of the liquids circulating through an eye is not followed by 
glaucoma arraigns all the explanations thereof which look to an 
increased pressure as in itself of essential importance in its causa- 
tion. Such considerations compel the conclusion that the 
cause of glaucoma resides in the tissues of the eye itself, and 
that it becomes glaucomatous not because fluid is pushed into 
it, but because through changes in it, it absorbs an increased 
amount. That the amount of such absorption is sufficient to 
explain the severest grades of glaucoma is clearly evidenced by 
the fact that through the mere presence of a little acid, a beef 
eye can be made to absorb enough water to rupture its enormously 
thick sclera. This is a grade of glaucoma that exceeds anything 
ever seen clinically. Our experiments further show that this 
increased absorption of water is dependent upon the colloids in the 
eye, for not only is it built up of aseries of different colloids (sclera, 
cornea, lens, vitreous humor), but the same conditions which govern 
the absorption of water by protein colloids also govern the absorption 
of water by the eye. On the ground of these experiments we can, 
therefore, no longer insist that an eye becomes glaucomatous because 
water is forced into it. It does this because chemical changes occur 
within it which increase the capacity of the ocular colloids for hold- 
ing water so that these are enabled to absorb water from any avail- 
able source. In our experiments with enucleated eyes this source 
is the solution into which the eye has been dropped; in the 
body it is the liquids flowing about or through the eye. 

The chemical changes in the eye which clinically lead to glau- 
coma are the same as those which may give rise to an oedema 
anywhere else in the body. In a large number of cases, circulatory 
disturbances in the eye are unquestionably present which per- 
mit of an accumulation of carbonic acid and of such other acids 
as are a constant accompaniment of states of oxygen want. In 
the glaucomas due to infections or, in general, to the toxic agents 
capable of producing " degenerative " or inflammatory changes 
(in the strict pathological sense of the term) in the eye we have 
to look to the chemical alterations thus induced for the cause of 
the altered hydration capacity of the ocular colloids. Many 



GLAUCOMA 



797 



of these intoxications lead to an altered oxidation chemistry in the 
affected tissues and an accumulation of acids; but the direct 
action of chemical substances (like urea or certain amins) , which 
in their ability to increase the hydration capacity of protein 
colloids act like acids, must also be kept in mind. Under the 
influence of proteolytic ferments, proteins having a low hydra- 
tion capacity can also be converted into such as have a higher 
one. Ordinary gelatin can thus be converted into Beta-gelatin. 
Wolfgang Ostwald's studies show Beta-gelatin to be capable 
of greater swelling than the unchanged. It is therefore con- 
ceivable that in inflammation (whether in the eye or elsewhere) 
an increased hydration capacity of the involved tissues may 
result from " autolytic " changes occurring in them even when 
no abnormal storage or production of acids in the part occurs. 
Perhaps the best evidence of the correctness of this colloid- 
chemical conception of glaucoma is furnished by the following 
clinical observations. 

II 

ON THE RELIEF OF GLAUCOMA 

1. Local Measures 

The experiments on the swelling of enucleated eyes famil- 
iarized us not only with ways and means by which an intense 
glaucoma can be induced in an eye, but showed how the develop- 
ment of such can be prevented, or, once established, be made to go 
down again. While under ordinary circumstances little is 
gained by simply reducing an oedema, there exist a number of 
clinical forms of it which are in themselves dangerous. Glau- 
coma is one of these, which through its existence for even a short 
time may permanently blind an eye. To be able to combat 
the oedema in such a case is, therefore, not a useless procedure. 

In the experiments on the swelling of eyes we learned that 
the presence of any salt markedly decreases the amount of 
water that an eye will absorb in an acid solution. The question 
therefore arose whether the instillation of salt solutions into 
the eye might not be followed by relief in clinical cases of glau- 
coma. 



798 



(EDEMA AND NEPHRITIS 



Hayward G. Thomas and I decided to test the matter. 1 
The instillation of salt solutions was not, however, to be entered 
upon hastily, for experiment had shown that while all salts 
reduce the amount that an eye will swell in an acid solution, 
a large number also increase its tendency to develop corneal 
opacities. There would be little gained, except so far as 
relief from certain subjective symptoms might be concerned, 
by guarding an eye from blindness through glaucoma while blind- 
ing it through the agency employed for its relief. There exist, 
however, a number of salts which inhibit markedly the swelling 
of eyes in acid solution and at the same time not only do not increase, 
but even decrease the tendency to the development of these corneal 
opacities. In other words, the use of these salts tends to prevent 
the development of even that well-known turbindess of the cornea 
which is so constant a sign in clinical cases of glaucoma, and 
which one never fails to get in the experiments on eyes that I 
have described. 2 These salts are the citrate, tartrate, sulphate 
and phosphate of sodium and potassium. 

After a number of preliminary tests sodium citrate was 
chosen as the salt best suited for clinical use. Only the 
chemically pure salt should be used, in concentrations 
varying from m/8 to m/6 solution. Expressed in percentage 
the former is equivalent to a 4.05 per cent solution, the latter 
to a 5.41 per cent solution of the ordinary crystallized sodium 
citrate. The m/8 solution has an " osmotic" pressure below 
that of the human tissue fluids, the m/6 one slightly above. 
The injections are made with a fine-needled hypodermic under 
the conjunctiva in the usual manner adopted by ophthalmol- 
ogists, and are preferably preceded by the use of cocain and 
adrenalin solutions. Enough of the sodium citrate is injected 
to distend gently the connective-tissue spaces (5 to 15 drops). 
Immediately following the injection the patient suffers some 
pain. While this is usually insignificant, it is fairly severe 
in certain cases. Alternate hot and cold compresses laid 
over the eye may help to ease it. In any event it dis- 
appears in a few minutes. In the severer cases of glaucoma 

Wayward G. Thomas and Martin H. Fischer: Annals of Ophthal- 
mology, 19, 40 (1910); Hayward G. Thomas: Journal of Ophthalmology 
and Oto-Laryngology, 5, 205 (1911). 

2 See the succeeding page 806. 



GLAUCOMA 



799 



we use the stronger sodium citrate solution, in the milder ones 
or for subsequent treatment the m/8 is sufficient. This will, 
in fact, rapidly reduce the tension in even the severe cases of 
glaucoma. Later in the treatment a mixture of one part of 
the m/8 sodium citrate solution, with two to four parts of a 
" physiological " (0.9 per cent) sodium chlorid solution, is 
sufficient. It need hardly be emphasized that such citrate solu- 
tions must be sterile and that since bacteria readily decompose 
them, they need constantly to be freshly prepared. Our results 
may be summed up as follows: 

Subconjunctival injections of m/8 to m/6 (4.05 to 5.41 per cent) 
solutions of the crystallized, chemically pure sodium citrate in 
clinical cases of glaucoma are harmless and always followed by a 
prompt fall in ocular tension. The fall may be appreciable within 
ten minutes after the injection and ultimately so great as to make the 
eye have a subnormal tension. The effect of such injections lasts 
from three to six days (or even more) and is accompanied by a 
relief of all the subjective symptoms of glaucoma (except, of course, 
any blindness due to permanent structural changes). 

2. Systemic Measures 

As the ophthalmologists have long recognized, many factors 
lying outside of the eye play a role in the development of the 
glaucomatous attack. The problem is, as a matter of fact, 
analogous to the acute cedemas that may develop in any of the 
other organs of the body, as in the brain (uremia), the kidney 
(nephritis), the optic nerve (papillo-cedema) , or the liver (cloudy 
swelling, liver necrosis). And as in such cedemas we err when 
we observe only the specifically involved tissues, so also in 
glaucoma. 

It is self-apparent that a hydrating agency such as an 
accumulation of acid in an eye leads to a swelling of the ocular 
colloids, no matter whether its origin is purely local (say the 
consequence of an arterio-sclerosis of the blood vessels of the 
eyeball), or whether to this local acid production is added the 
effect of acid produced elsewhere in the body and carried into 
the eye through the circulation. 

The conditions that lead to an abnormal production or 
accumulation of acid in the body as a whole are many, and 



800 



(EDEMA AND NEPHRITIS 



constitute a list that is familiar to every ophthalmologist under 
the heading of etiological factors concerned in the production 
of glaucoma. Starvation, an excessive protein diet, hard muscular 
and mental work, excessive consumption of sour wines, various 
intoxications (anesthetics, alcohol, arsenic), the infections, the 
severe anemias, generalized arterio-sclerosis, uncompensated heart 
lesions, exposure to cold, are all associated with an abnormal 
production or accumulation of acid in the body. Any of these 
may be the deciding factor that pushes an eye on the verge of 
glaucoma from a local condition, over the line, and so precipi- 
tates the glaucomatous attack. 

Local treatment alone, be this a subconjunctival injection of 
sodium citrate or one of the more popular iridectomies, sclerotomies, 
or trephinings, does not affect the contributions which are being made 
by the extraocular factors. To meet the situation we must treat 
the whole man. 

To begin with, it is clearly indicated, therefore, that we 
remove as many as possible of these extraocular conditions. But 
we are likely to find that some of them cannot be removed, or 
at least not with sufficient speed to make it count in our patient 
who finds himself in the midst of a glaucomatous attack. Under 
these circumstances we have only one other door open to us, 
and that is to combat their consequences. In practical terms 
this again means a neutralization of the abnormal acid content 
by giving alkali; the administration of salts to reduce the swelling 
of all the colloids in the body including those of the eye; and an 
administration of carbohydrate if indicated. 

How in actual practice this is accomplished may be illus- 
trated by the following history of a case of glaucoma which Hay- 
ward G. Thomas invited me to see. 

Case XXVIII. — Mr. F. C, aged seventy-two, goes to his office daily. 
He has for fifteen years had some albumin and casts in his urine. Unless 
his carbohydrates are consumed in moderation, he also has sugar. All 
his superficial arteries are easily palpable and tortuous, and his heart is 
hypertrophied. The second heart sound is accentuated. His blood 
pressure is constantly 190, and rises to 210 mm. of mercury. He has 
never had a generalized oedema. 

On July 16, after a day of mental and physical fatigue, he developed 
pain in his left eye and left temple, noticed that his eye was "bloodshot,", 
and that he could not see the outline of objects clearly. The condition 
Continued through the night, the pain being so severe as to keep him 



GLAUCOMA 



801 



awake. In the morning of July 17 his state had not improved, and his 
eyesight had fallen off still more. He tolerated his condition through- 
out this day, and through the succeeding night and day, by which time 
he declared himself completely blind in the affected eye. 

In the middle of the afternoon of July 18 he summoned Dr. Thomas, 
who found the eye hard (tension +3), pupil dilated to size 5, Morton 
scale, conjunctiva very much chemosed, cornea slightly steamy — a 
typical attack of the so-called " acute inflammatory glaucoma." Instilla- 
tions of eserin were at once begun, and the patient moved to the hospital. 
The instillations were entirely without effect. 

At 9 p.m. a slow injection of the following solution into the rectum 
was started: 

Sodium carbonate (monohydrated, Na 2 C03-H 2 0).. 4.3 grams . 

Sodium chlorid 14.0 grams 

Distilled water, enough to make 1000 cc. 

The patient retained the solution well, and by midnight had taken up 
the whole liter. The tension in the eye had fallen appreciably an hour 
after the injection was started, and at midnight was normal to the touch. 
At the same time the subjective symptoms of the patient improved, 
and he went to sleep. At 4 a.m., 500 cc. more of the above formula 
were injected and retained. At daybreak the patient was able to 
recognize gross objects, and through the day his vision became steadily 
clearer. He remained under observation in the hospital for two days 
longer. No new symptoms developed, and he was discharged with 
completely restored vision. 

In interpretation of the clinical history just detailed, which 
is characteristic of the larger number of glaucomas encoun- 
tered in patients beyond forty, I would say that vascular disease 
was primarily responsible for a diminished oxygen supply to 
the eye. For years such a change had led to no appreciable 
symptoms so far as the eye was concerned, but one day in con- 
sequence of unusual muscular and mental fatigue, aided possibly 
by an " acidosis " incident to his sugar intolerance, the acid 
accumulation from these sources added to that initially incident 
to the bad blood supply to the eye, sufficed to increase so materi- 
ally the hydration capacity of his ocular colloids that they swelled 
to the point of giving him easily recognized signs and symptoms — 
a frank oedema of the eyeball, a glaucomatous attack. But the 
reduction of this attack did not change his blood vessel disease, 
and so it could safely be predicted that in consequence of another 
period of hard work or dietary indiscretions he would again get 
eye symptoms. 



802 



(EDEMA AND NEPHRITIS 



As a matter of fact, Dr. Thomas reports that after two months 
of freedom from symptoms the patient tired of his restricted 
activities and his alkalinized diet and had two more attacks of 
increased tension, though not of a severe type. The first of these 
was controlled by the same eserin solution which in the initial 
severe attack had been unable to reduce the tension. In the 
second of these milder attacks the eserin again proved unavail- 
ing, even though a contraction of the pupil resulted. An active 
administration by mouth of alkali and table salt with calomel 
and magnesium citrate was turned to, and while using these the 
tension returned to normal. 

When we have succeeded in relieving the frank glaucomatous 
attack in which we are likely first to see our patient it becomes 
our purpose to prevent further attacks. To do this we make use 
of the principles already enunciated, though it is not necessary, 
of course, to work so aggressively. We need again to recognize 
and avoid as far as possible those conditions which directly 
or indirectly threaten to increase the hydration capacity of the 
ocular colloids and to increase the margin of safety against such. 
This means a sane restriction of the physical and mental activities, 
a careful control of the water intake and a quieter insistence on a 
diet rich in alkalies and salts. 

Ill 

SOME COMMENTS 

Prompt as may be the relief of tension with its associated 
symptoms in glaucoma after subconjunctival sodium citrate 
injections or the use of alkaline hypertonic salt solutions by 
rectum, it must be clearly understood that neither of these con- 
stitute a "cure" for it. As a cure of glaucoma we could only 
consider a removal of the condition or conditions which are 
responsible for the development of the substances which increase 
the hydration capacity of the ocular colloids. If these are 
acids, the product of a circulatory disturbance or of an infection, 
then clearly the real cure resides in a correction of the circula- 
tion to the eye, or in the removal of the infection. But even 
toward such ends do these dehydrating methods help. In the 
progressive development of a glaucoma the swelling of the col- 



GLAUCOMA 



803 



loids tends to compress the blood vessels passing into and out 
of the eyeball. The natural tendency of a glaucoma is, therefore, 
to make itself worse. Writers on ophthalmology are in the 
habit of laying great stress on the obliteration of the filtra- 
tion angle. Obliteration of the filtration angle is frequently said 
to be the cause of glaucoma. It is a consequence, as evidenced 
by the fact that enucleated eyes rendered artificially glaucom- 
atous by being placed in acid solutions show the same 
progressive decrease in the depth of the anterior chamber that 
is noted in clinical cases. The matter is easily explained through 
the unequal swelling of the different colloids of the eye, those 
posterior to the lens (sclera, choroid, vitreous) being capable 
of greater swelling than those anterior to it (cornea, aqueous) . 

Through this unevenness in swelling the cilary body is crowded 
against the sclera — a process in which the blood vessels of the 
ciliary body become pinched. The resulting embarrassment 
in the circulation (with its lack of oxygen, accumulation of 
carbonic and other acids, etc.) is then added to whatever £on- 
ditions are already active in producing the glaucoma. To 
reduce the swelling of the ocular colloids, even though but tem- 
porarily, is, therefore, to improve the circulation through the eye 
and in this way to contribute not inconsiderably toward the 
restitution of normal conditions within it. If the glaucoma 
is the consequence of some acute accident then its prompt relief 
may not only save the eye from blindness through pressure, but 
by helping toward the re-establishment of a normal circulation 
through the eye furnish the necessary conditions required for 
the repair of any pathological process. 

The principles underlying both the local therapy of glau- 
coma (subconjunctival injections of sodium citrate) and the 
general therapy, as touched on here, are of course the same, 
and so the fact will not prove strange that both produce a lower- 
ing of tension. I now urge and rely chiefly on the withdrawal of all 
water intake by mouth and the use of the rectal injections of 
hypertonic alkaline solutions (either the sodium carbonate-sodium 
chlorid solutions or the strong sodium bicarbonate solution recom- 
mended above) while teaspoonful doses of saturated magnesium 
sulphate solutions are given by mouth at hourly intervals for four 
to eight doses. This regimen is followed not alone because glau- 
coma is so often but a local expression of a general state, but 



804 (EDEMA AND NEPHRITIS 

because, while various observers 1 have reported uniformly favor- 
able results from the use of sub-conjunctival injections of sodium 
citrate, others have objected to them, and some have even main- 
tained that their use increased the tension. 2 "While I have myself 
never observed such a result, the proper use of alkali and salt by 
mouth and rectum produces so effective a dehydration of the body 
(including the eye) that I have in the past seven jxars made it a 
rule to try first this simpler method for two or three hours before 
turning to subconjunctival injections. But whatever scheme is 
used let me here again insist that the various mixtures of alkali 
and salt, and sugar and water which I have suggested and to which 
my name is often linked have not in themselves any special virtue. 
Virtue resides in working out a really effective scheme for dehy- 
drating swollen colloids, and the attending physician or surgeon is 
at liberty to accomplish this by any means which he thinks best. 3 

Some of my critics have utilized their failure to obtain a fall 
in tension after subconjuctival sodium citrate injections to com- 
bat' the colloid-chemical theory of glaucoma. Without charg- 
ing them with improper preparation or improper use of their 
solutions — I find men constantly modifying the concentration or 
the amount of the injection to suit themselves — it might be 
well to inquire why they failed. 

When a solution of sodium citrate is injected subconjunctivally, 
we desire to have the sodium citrate diffuse into the eye and so 
decrease the hydration capacity of the ocular colloids (shrink 
them) . We use water along with the salt only of necessity. But 
if the glaucoma is of a severe type it means that the hydration 
capacity of the ocular colloids is exceedingly high. It may hap- 
pen in consequence that when we inject an aqueous solution 
subconjunctivally the water is absorbed before the salt gets in, 
in which case the swelling would actually be further augmented. 
The bad result is not due to the sodium citrate, but to the 
inability to get the salt into the eye in sufficient concentration. 
Or, if extraocular factors are playing a good part in the produc- 

1 See for example tax der Hoeye: Klin. Monatsbl. f. Augenheilk. N. 
F., 13 ; 602 (1912). 

2 See Gilbert: von Graefe's Arch. f. Ophth., 32, 438 (1912). 

s Decrease in intraocular tension has been accomplished by R. T. Wood- 
yatt, W. D. Sansum, and R. M. Wilder (Jour. Am. Med. Assoc:, 65, 2067 
(1915); ibid., 68, 1885 (1917)) by injecting intraveneously strong dextrose 
solutions. 



GLAUCOMA 



805 



tion of the glaucoma as is the case when there is a generalized acid 
accumulation resulting from a weakened heart, overwork, starva- 
tion, etc. ; this cannot, of course, be neutralized by the instilla- 
tion of a few drops of some salt solution under the conjunctiva. 

Others of my critics have objected to the lack of tonometric 
readings in my reports. A desire always to substitute actual 
figures for the results of human judgment together with the easy 
availability of the Schiotz tonometer certainly tempts one to 
fill out this gap, and yet I have hesitated in this direction, and 
for the following reasons. First, the reduction of tension in an 
eye must be of so marked a character if it is to serve as the basis 
for a suggested therapy that it must be readily discernible 
even to the, perhaps, but slightly practiced touch of any physi- 
cian. I would think little of a suggested therapy for glaucoma 
which reduced tension so slightly that only a tonometer could 
recognize the change. Second, tonometric measurements cannot 
be made without instillations of cocain, holocain or similar 
substances into the eye, and manipulations of the eyeball which 
are not without effect. Such instillations and manipulations 
themselves lead to an increased cedema, and so tend to main- 
tain or augment whatever increased tension already exists in 
the eye. 

There is evidence of a marked tendency in the recent literature 
on the treatment of glaucoma to urge more strongly than for- 
merly the use of myotics and constitutional remedies for the 
relief of glaucoma. This has largely grown out of the fact 
that iridectomy all too often fails to give more than temporary 
relief. The problem is really the same as that encountered in 
brain oedema, in nephritis, etc., which represent in the involved 
organs processes which if they affect the eye are called glaucoma. 

A decompression operation, a stripping of the capsule, etc., 
may bring clinical relief (by permitting a better circulation through 
the swollen parts), as do sclerotomy, trephining, and similar sur- 
gical procedures when applied to the eye. But statistics on the 
after effects of operations in glaucoma are no better than those 
following surgical interference in brain cedema, nephritis, etc. 
The reasons for these failures, as well as the explanation of the 
occasional brilliant result, are, of course, not far to seek. 

Behind an cedema of the eye lie the same possibilities which 
produce an cedema anywhere else in the body. Rarely are 



806 



(EDEMA AND NEPHRITIS 



such confined to the eye alone. And the effects and relative 
merits of a surgical operation, or a myotic, or sodium citrate, or 
alkali and salt by rectum can be foretold here as well as when a 
capsule stripping, a vasodilator, a diuretic salt or alkali are 
used in a brain oedema or a nephritis. When the swelling of the 
eye is due to a temporarily acting poison all may yield brilliant 
and permanent results, for when the tension has once been 
reduced the eye is saved, for the causes leading to the oedema 
have then also gone. But when blood vessel disease — by far the 
commonest cause in our older 'patients 1 — is responsible for the 
increased tension, it may again be reduced, but since this does 
not abolish the blood vessel disease, the tension is again liable to 
increase even if an iridectomy or a trephining has been done or 
alkali and salt have been properly used. 

Many ophthalmologists know now and all will shortly learn 
that a diagnosis of glaucoma is as complete as a diagnosis of 
" dropsy," and as modern medicine is not content with the latter 
it will not long remain so with the former. 

Glaucoma, except when it follows trauma or direct infection, 
is not a local disease but nearly always a local expression of 
systemic derangement. It will be blotted off the pages of 
ophthalmic literature not by more surgery but by a prophy- 
laxis and therapy which recognizes and treats vascular disease, 
infection and intoxication involving the eye. 

IV 

ON THE NATURE OF CORNEAL OPACITIES 

In clinical cases of glaucoma there is noted as one of its most 
constant signs more or less opacity of the cornea. In an entirely 
similar manner the cornea loses its transparency in the experi- 
mentally induced glaucomas already described. Since the 
essential change in the eye in glaucoma consists of an abnormal 
increase in the amount of water held by it, the view generally 
advanced by ophthalmologists that the observed opacities are 

1 In 22 patients with glaucoma 19 showed high blood pressure and other 
frank signs of vascular disease. The remaining 3 were younger individuals 
who had suffered from "rheumatism," with metastatic, infectious involve- 
ment of the eyes themselves. The eyes of one of these had been operated 
upon 13 times without benefit. 



GLAUCOMA 



807 



due to the absorption of water by the cornea does not surprise 
us. Such an origin for the opacities observed here has been ex- 
tended to include those found in the other transparent media of 
the eye. Especially has the lens been believed to owe its loss 
of transparency in many conditions to an imbibition of water. 

Serious objections seem never to have been raised against 
such a view, and this in spite of the fact that clinical cases of 
absolute opacity of the cornea or the lens may exist without 
any evidence of an increased absorption of water, while, on the 
other hand, even severe cases of glaucoma may come and go 
without more than a mere haziness of the cornea. 

These paragraphs confine themselves to the question of the 
origin of corneal opacities, simply because these have been 
studied with greatest care. It seems, however, that what is here 
said regarding the cornea holds also for the lens 1 and the other 
transparent media of the eye. The opacities referred to, it need 
hardly be said, include only such as are the consequence of 
chemical disturbances in the eye, and have nothing to do with 
such as are the result of leucocytic deposits, connective tissue 
scars, etc. 

Neither the presence of an increased or a decreased amount of 
fluid in the cornea is responsible for the appearance of an opacity. 
Such is produced whenever some of the colloid constituents of the 
cornea are precipitated, and depending upon whether the precipita- 
tion is only slight or very great, these opacities vary from being 
barely visible (steaminess of the cornea) to such as are intensely 
white (leukoma) . 

The effect of different solutions on the transparency of the 
cornea was judged in two ways, first in regard to the rate at which 
they permitted the development of an opacity, and second, 
in regard to the intensity of the opacity. The outer limits of the 
former vary from a few minutes to several days, for the latter 
from a turbidness scarcely visible to the naked eye to a white- 
ness like that of boiled albumin. The italicized conclusion is 
based upon the following facts. 2 

1 For experimental details which may all be explained in the terms of 
colloid- chemistry on opacities of the lens and water absorption by it, see 
Phil. Botazzi and N. Scalinci: Arch. ital. Biol., 51, 96 (1908); Rend, 
della Accad. dei Lincei, 27, 305, 445, and 566 (1908); ibid., 28, 225, 326, and 
379 (1909). 

2 See Martin H. Fischer: Pfliiger's Arch., 127, 46 (1909). 



808 



(EDEMA AND NEPHRITIS 



(a) If an eye is simply allowed to dry, no opacity of the 
cornea develops. Mere loss of water, therefore, does not lead 
to its appearance. 

(b) If an eye is laid in distilled water it gains in weight. In 
this process of water absorption the cornea takes a prominent 
part, yet no turbidness of this structure develops until quite 
late. Simple absorption of water, therefore, does not lead to an 
opacity. 

(c) The presence of any acid favors the development of an 
opacity, but the different acids are unequally powerful in this 
regard. Nitric acid induces a corneal opacity more quickly 
than an equinormal oxalic acid, and this more quickly than an 
equinormal hydrochloric acid. Still less powerful are sulphuric 
and acetic acids in the order named. Clearly, therefore, the 
order in which acids induce corneal opacities is entirely different 
from the order in which they make eyes swell. 

(d) We note a further discrepancy between the amount of 
water absorbed by an eye and the rate of development, or better, 
the intensity of a corneal opacity as soon as the effects of adding 
equimolar salt solutions of different kinds to any acid solution 
are compared. While every salt reduces the amount of water 
absorbed by an eye in an acid solution, some salts favor the 
development of an opacity while others distinctly inhitit it. 
The citrate, acetate, and sulphate, for example, inhibit the 
development of a corneal opacity, while the sulphocyanate, 
nitrate, bromid, and chlorid favor it. 

(e) The effect of any salt seems to be made up of the algebraic 
sum of its constituent radicals. When a series of salts having 
a common base are compared, the order of the acid radicals is 
always the same, and when a series of salts having a common 
acid are compared, the order of the basic radicals is always the 
same. These orders are indicated in the two following lists, 
in each of which the radical most effective in producing an opacity 
is given first, that most effective in inhibiting it last. 

Sulphocyanate, nitrate, bromid, chlorid, sulphate, acetate, citrate. 

Iron (ferric), copper (cupric), calcium, strontium, barium, magnesium, 
ammonium, sodium, lithium (?). 

The order in which different salts or, as we had best say, 
their constituent radicals, affect the production of corneal 



GLAUCOMA 



809 



opacities, is, therefore, an entirely different one from the order 
in which they influence the amount of water absorbed by the 
eye as a whole. The disproportion is illustrated in Fig. 217. 

In a is shown the thickness of the cornea of an eye which has 
lain in distilled water for thirty-six hours and is still perfectly 
clear; in b that of an eye which has remained for the same 
length of time in n/110 hydrochloric acid. This eye burst 
six hours after being placed in the solution. The cornea is 
very thick, but only slightly opaque (ground-glass appearance). 
c was left for thirty-six hours in a similarly concentrated hydro- 
chloric acid solution, containing magnesium nitrate in addition 
(20 cc. n/10 HC1+200 cc. m/3 Mg(N0 3 ) 2 ). Even though the 




c 



Figure 217. 

cornea is not swelled — it is even thinner than normal — it has 
the intensely white color of boiled albumin. About the same 
condition of affairs is shown in d, which indicates the appearance 
of an eye thirty-six hours after being placed in n/110 hydro- 
chloric acid solution plus ferric chlorid (20 cc. n/10 HC1+200 



810 



(EDEMA AND NEPHRITIS 



cc. m/3 ferric chlorid). In spite of the great loss of water, the 
thin cornea is intensely white (and stained slightly yellow from 
the iron chlorid). 

(/) In the experiments on the swelling of eyes it was found 
that non-electrolytes in low concentration do not markedly 
affect the swelling of eyes in an acid solution. Nevertheless, 
most non-electrolytes appreciably inhibit the development of 
corneal opacities. 

(g) All the above facts show clearly that no parallelism 
exists between the total amount of water absorbed by the cornea 
and the intensity or rapidity of the development of an opacity 
in it. The facts outlined are easily harmonized as follows: 
While the eye as a whole swells, due to an increased hydration 
capacity induced in some of its colloids, a second colloid (of the 
type of casein) is being precipitated (dehydrated). A swollen, 
eyeball with opacities in its clear media (glaucoma) is the analog 
of what in other organs is known as " cloudy swelling " 1 and the 
conditions which bring it about are exactly the same in both. 

V 

CLOSING REMARKS 

This volume must not be ended without the request that 
should its contents tempt any clinician to try the therapeutic 
methods here advocated, it tempt him also to study the considera- 
tions upon which they are based. It will prevent misunderstand- 
ing in criticism, and the disappointment incident to application 
of the suggested remedial measures to improperly chosen Clinical 
cases. 

Our studies 2 were made originally with an eye to analyzing 
in the terms of colloid chemistry a series of physiological and 
pathological phenomena which are associated with the protlem 
of water absorption, and with no immediate ideas of applying 
clinically any of our deductions. We think that we have suc- 
ceeded in showing that the water of the body cells and fluids 
is carried as hydration water in combination with the hydro- 

1 See page 540. 

2 For references to them, see the bibliography at the end of this volume. 



GLAUCOMA 



811 



philic, more especially the protein colloids found in them. We 
have extended this view to include cedema, which we have defined 
as a state in which the hydration capacity of the body colloids 
is abnormally increased. As causes of cedema we have cata- 
loged any substance or condition which is capable, under the 
circumstances existing in the body, of increasing the hydration 
capacity of any of its hydrophilic colloids. We have mentioned 
that an abnormal production or accumulation of acids constitutes 
one of these conditions, but in spite of its dominant role we have 
never maintained this to be the only one. As we discovered that 
all salts, including the neutral salts, decrease the hydration 
capacity of certain proteins swelling in the presence of an acid, 
it is but natural that we should have insisted that use of such a 
fact could and should be made in combating the increased 
hydration which in the body we call cedema. And since such an 
cedema, as it involves special cells, special organs, or the body as a 
whole, goes by many names, it is only natural and logical that we 
should have proposed the same principles for the treatment of 
all of them. 

Upon such considerations, learned in the laboratory and 
upon animals where alone we can obtain strictly reproducible 
results, is based all that we have tried to formulate into some 
principles that should guide us in the treatment of those clinical 
conditions in which an cedema is a prominent feature, and inde- 
pendently of whether it involves the whole body or individual 
organs like the skin, mucous membranes, kidney, brain, liver, 
eye, or optic nerve. 

I do not believe that these fundamental propositions have 
been or can be validly attacked. Progress will be furthered 
by those who make the more positive contributions which tell 
us how chemically or physically conditions are brought about 
in any organism which alter the hydration capacity of its con- 
stituent colloids. In this problem, as always, science will be 
moved less by the cry of what is not, than by the whisper of what is. 



APPENDIX 



PART EIGHT 
APPENDIX 



I 

THE RELATION OF MOUTH INFECTION TO SYSTEMIC 

DISEASE 1 

1. Introduction 

I am sure that the medical profession has never pressed home 
the importance of good teeth and their preservation as effectively 
as has the dental profession. In fact, the dentists have succeeded 
so well that it is at this time almost impossible to find a patient who 
will submit to an extraction or a dentist who will do it. I am not 
here to urge a return to pristine methods. The only question that 
I am going to discuss is that of whether we have allowed the pendu- 
lum to swing too far. We do not want to go back to the age when 
we lost our teeth easily. On the other hand,, from the very fact 
that we do not now do so, a serious new problem has arisen. Is the 
mere preservation of the teeth to remain the first consideration, or 
does not this in many instances become a menace to our general 
health? To the discussion of this more modern question the den- 
tists have also contributed much. They have told us times with- 
out number how close is the relation between unclean mouths, 
between diseased conditions about the teeth and systemic disease, 
but because their proofs have rested so largely upon clinical evi- 
dence alone not everyone has been convinced. In clinical observa- 
tion so much depends upon the judgment of the observer, and there 
is always so much slippery ground, that the conservatism which 
makes most of us skeptics is in good part justified. 

It marks a great step forward that a number of scientific 

1 Republished with additions from the stenographic report of an address 
first given to the Cincinnati Dental Society, January 29, 1915, and first 
published in the Dental Summary, 35, 607 (1915). 

815 



816 



(EDEMA AND NEPHRITIS 



researches fathered by that master mind in medicine, Frank 
Billings, 1 and worked out in their clinical, bacteriological and 
therapeutic aspects by his associates and assistants have brought 
unequivocal proof for what many dentists long suspected and 
what some medical men have taught, namely, that there is a 
most profound relationship between certain diseased conditions 
about the mouth and systemic disease. Now, why is this ques- 
tion, as a general problem in medicine, so important? The answer 
is, I think, found in the following: 

Within the years that all of us have' been working in medicine 
we have seen two great changes come over the world. First, we 
have found the average length of life per individual gradually to 
increase; second, we have seen the causes of death decrease in 
certain categories while increasing in others. There is, for ex- 
ample, an agreeable falling off in the deaths due to typhoid, to 
cholera, to small-pox; an increase, on the other hand, in the num- 
ber of heart and kidney deaths, of those due to arteriosclerosis, 
and of deaths due to certain other causes too frequently regarded 
as the necessary accompaniments of "old age." We shall return 
to this problem later but even here I should like to emphasize 
that old age is, in my opinion, not so much the cause of these 
pathological changes, as these are the cause of old age. There is a 
physiological death, but I question very much, judging simply 
from the people and patients that I have seen, whether this ever 
occurs below ninety or a hundred years. But if we no longer die 
of the old causes — and we do not — then what is it that does carry 
us away in our forties and fifties and sixties? "Barring gross 
accidents and such things as cancer — of the true nature of which we 
as yet know almost nothing — we now die very largely of the direct 
or indirect consequences of low grade infections, the nature of 
which is only just becoming clear. And since these infections 
must have a beginning and must come from somewhere, and since 
a part of this somewhere is in the mouth, as we shall see, we have 
every reason to feel an interest in this discussion. 

The truth of all this will come home to you more clearly as we 
proceed. We do not die of acute scarlet fever, of acute typhoid, of 

i Frank Billings: Arch. Int. Med., 4, 409 (1909); ibid., 9, 484 (1912); 
Jour. Am. Med. Assoc., 61, 819 (1913); ibid., 63, 899 (1914); Forchheimer's 
Therapeusis of Internal Diseases, 5, 169, New York (1914); Focal Infection, 
New York (1917). 



APPENDIX 



817 



acute pneumonia, as much as we used to, but most do not yet die 
physiologically. In our city, for example, there used to be several 
hundred typhoid victims with many deaths every year; and now we 
can hardly find one to demonstrate to our medical students. But 
consider for a moment the necessary corollary of all this. Evi- 
dently those who have been spared from typhoid are saved up for 
death by another cause, and it is for us to ask what these newer 
causes are. The present-day point of view in medicine is on this 
account alone a totally different thing from what it was a score of 
years ago, for our medical problems, in their quantitative relation- 
ships if in no other, are now totally different from what they once 
were. 

And yet we shall observe that even these newer deaths are 
still attributable to the enemies that harassed us before, only they 
are less virile. The victims still die, in other words, of infections, 
but they are subtler in type. Where do these subtler things come 
from? They are systemic infections very largely, as we shall 
find, but they spring from local causes, which, because they are at 
times very small, have been and still are largely overlooked. 

2. Historical Remarks 

The so-called specialists in medicine have, of course, frequently 
called our attention to the close association between disease in 
particular divisions of the body and disease elsewhere in the 
organism. Thus, the aurists and rhinologists have long empha- 
sized the important relationship between infections of the ear or 
nose and infections of the brain and its meninges. The gynecolo- 
gists have long known that infections spreading through the fallo- 
pian tubes are the frequent cause of local or generalized peritonitis, 
while infections of the uterus are commonly the source of general- 
ized infections. A great many women, for instance, who do not die 
of the acute childbed fever so common years ago, still die of this 
but in the subtler form which is all too frequently overlooked. 
Subacute infections starting in the lacerated uterine tissues may 
spread into the circulation to move with the circulating blood 
throughout the body. It is just such types of low-grade infec- 
tion that we are going to discuss. The genito-urinary special- 
ists have also noted the important relation existant between 
infections of the organs with which they deal and systemic disease. 



818 



(EDEMA AND NEPHRITIS 



I remember when the gonococcus was first recognized as capable 
of giving rise not only to a local infection, but to a systemic one as 
well. From a local focus the gonococcus may spread into the 
general circulation thus yielding ultimately, if the organism locates 
in the heart valves, an endocarditis, or, if it locates in the joints, 
a so-called gonorrheal rheumatism. 

The dentists, too, have taught us many lessons in this regard. 
They have repeatedly emphasized the important connection 
between trouble in the mouth and systemic disease. William 
Hunter, in England, preached this lesson, and none ever did it 
better than M. H. Fletcher of our own city. Fletcher was 
the first to convince me that a diagnosis of trifacial "neuralgia" 
never meant anything. Of course, some medical men had sus- 
pected this in some cases, but most held then and some still hold, 
to a neuralgia sui generis. Well, neuralgia means pain in a nerve, 
and is just as complete a diagnosis as headache or toothache. The 
time has come when we are justified in raising our eyebrows and 
praying for the patient whenever a doctor diagnoses a case as 
neuralgia and stops content. The neuralgia is a symptom express- 
ive of pathological change in the involved nerve, due to intoxi- 
cation or a true inflammation, and many a one as it involves the 
nerves of the face is but the expression of an intoxication or an 
infection, traveling up the fifth nerve from a bad tooth. 

Of thirteen cases of trifacial neuralgia which Fletcher studied, 
he relieved twelve by proper treatment of infections about the 
teeth. I like to compare with this record that of some of my sur- 
gical friends, who have handled the same distressing condition in 
other ways. A popular method with them is to pull the fifth nerve 
out by the roots. In other words, the telephone bothers them, so 
they rip out the line. They have other ways also of handling the 
situation. Instead of recognizing the origin of the trouble and 
locating it (as is commonly the case, in the teeth) the surgeons kill 
the nerve, or paralyze it with alcohol. 

3. Infections of the Blood Stream and Systemic Disease 

The researches of the last twenty years have slowly forced home 
to us the enormous number of times that we get, in various diseases, 
infections of the blood stream, in other words, states in which 
showers of micro-organisms invade the circulating fluids of the 



APPENDIX 



819 



body. We used to think that everybody thus attacked, in other 
words, every victim of a bacteremia, was doomed to die. When I 
was a medical student — blood cultures were just becoming com- 
mon then — a positive finding was practically synonymous with a 
fatal prognosis. We have gotten over that notion, and as our 
methods for discovering bacteria in the circulating blood have 
improved, we have gradually found a whole list of infections in 
which there is at some time in the period of the disease an invasion 
of the blood stream. 

One of the first in which such invasion was recognized was 
typhoid fever. Originally, the typhoid bacilli were cultivated 
from the feces. They were next isolated from the Peyer's patches, 
and at this time it was quite generally held that typhoid fever was 
essentially a disease of these patches from which soluble toxic 
products spread into the circulation to produce systemic effects. 
But soon the typhoid organisms were isolated from the urine, 
from the rose spots, from the saliva, and finally, from the blood 
itself. When the blood itself was found invaded, it ceased to 
appear strange that the typhoid organism might be isolated from 
any of the organs and all the secretions of the body. Our concep- 
tion of typhoid fever thus changed completely from that in which 
it was considered a local disease of the Peyer's patches with 
systemic toxic effects, to one in which it was regarded as a systemic 
invasion with typhoid bacilli, from which various local evidences of 
disease might arise. Localizing in the lymphoid tissues of the 
body, it gives rise to the swollen and ulcerated Peyer's patches 
and to the enlarged spleen; localizing in the skin, it gives rise to 
rose spots; passing through the kidney, it may yield evidences of 
a nephritis. 

Shortly after these discoveries were made, similar facts were 
found true of the pneumococcus. We used to think that lobar 
pneumonia was essentially a disease of the lung, and as starting 
here. But as these patients were examined more carefully, it 
was found that the organisms responsible for the lobar pneumonia 
not infrequently circulated in the blood. With improved methods 
of examination it was soon found that practically every lobar 
pneumonia victim had the pneumococcus circulating in the blood 
at some time in the course of the disease. We have in consequence 
largely given up the old inspirational theory of lobar pneumonia, 
and now regard it more as a disease which is in essence an invasion 



820 



OEDEMA AND NEPHRITIS 



of the blood stream, with marked local manifestations in the 
lung. 

The same general truth was brought out for plague, by our 
fellow-citizen, William B. Wherry. 1 We used to distin- 
guish sharply between the pneumonic type of plague (which we 
held to be due to inspiration of the plague bacillus) and the bubonic 
form (which we held to be consequent upon the introduction of 
the organism somewhere into the lymphatic streams of the body. 
Wherry was able to isolate plague strains, which, when injected 
into the general circulation of animals, would localize in the lungs, 
in one group of instances, and give the animals a pneumonic plague, 
while in another, they would localize in the lymphatic tissues and 
give rise to a bubonic form. In other words, blood infection is 
really common to both; the peculiar manifestations of the disease 
depend upon the type of organism, this in its turn determining 
which clinical expression of the disease shall spring from the gen- 
eral blood infection. 

The subject before us deals with this same problem of blood 
stream infection and tissue localization, though the organisms 
which we shall discuss will be of a more ordinary variety. For 
the most part our remarks refer to the streptococcus, though 
several if not many other types of organism will shortly be found 
to belong in this same category. 

What, in the first place, is the character of the infectious organ- 
isms which invade the blood stream to give rise to the disturbances 
to be discussed? Generally speaking, they are of a rather low 
grade of virulence. Applied to the specific example of the strep- 
tococcus group of organisms, this means the following. 

The streptococcus that we learned to know as students typified 
the most virulent of the various infections that harass mankind. 
We used to describe the symptoms following infection therewith 
as of sudden onset and characterized by high fever, great prostra- 
tion, high leucocytosis, and, very frequently, early death. At 
least a part of the " hospital gangrene" of the Civil War was of 
this streptococcic type, which would go through a hospital like 
fire and burn out every ward in it. There is a great difference 
between this old picture and that of the streptococcus as we know 
it to-day. We now know streptococcus infections which show no 
fever, no leucocytosis and only a moderate invalidism. It must, 
1 William B. Wherry: Personal communication (1906). 



APPENDIX 



821 



however, be clearly remembered that if we look sharply enough, we 
will frequently find even in these aberrant cases many things to 
help toward a correct diagnosis. Between the two extremes 
there exist all possible transitional types. Patients with these 
low-grade infections are commonly of the ambulatory type. They 
have days of acute illness, of " biliousness" ; they may be filled 
with aches and pains; they drag along for weeks, months and years, 
never very ill, but never well either. They are often anemic, 
frequently adjudged neurasthenic, many times hypochondriacal. 
In this way they may live out what looks like their allotted number 
of days, though not infrequently the more spectacular manifesta- 
tions of a gastric hemorrhage, of gall bladder disease, of appendici- 
tis, of endocarditis or an acute kidney attack may close the scene. 

What has happened to the streptococcus we used to know that 
permits it to play these new and varied roles, for, as we shall see, 
it is still this organism that is chiefly responsible for the clinical 
pictures we have drawn? The organism, because of changes in its 
environment, has changed many of its old-time qualities. Instead 
of the one streptococcus we used to know, we now recognize a 
whole family of them which vary in their properties, from those 
practically avirulent to such as are of classic type, with the high 
virulence that we have already discussed. 

4. Modification of Micro-organisms through Environment 

This question of the modification of the qualities of micro- 
organisms through environment, has also received detailed study 
only in the last years. It is a little appreciated fact that our 
colleague, William B. Whekry, is again responsible for what 
are the most fundamental contributions in this field. Some 
fifteen years ago, he showed that the cholera-red reaction which 
is typical of the spirillum of this disease depends upon the kind of 
medium in which the organism is grown. 1 If it cannot produce 
a nitrite out of the medium in which it lives, this so-called cholera- 
red reaction does not develop. Here we have the development of 
a certain substance giving rise to a typical bacterial reaction, 
dependent absolutely upon the nature of the culture medium 
in which the organism is made to live. 

As familiar to you, there occasionally appear in tubercle bacilli 
1 William B. Wherry: Jour. Infectious Dis., 2, 436 (1905). 



822 



(EDEMA AND NEPHRITIS 



what are called "spores." They are not true spores, but they 
are called such because they look like them. Their development 
also depends upon the character of the medium in which the micro- 
organisms are grown. Wherry 1 has been able to produce the 
"spore "-bearing type of tubercle bacilli and the ordinary form at 
will, by simply varying the composition of the culture medium. 
Still more interesting, he has also been able to vary that property 
upon which depends, under ordinary circumstances, the very 
recognition of the tuberculosis group, namely, their so-called acid- 
fastness. The tubercle bacillus after being stained by certain 
dyes is not decolorized, as you know. This acid-fastness can be 
varied at will, depending upon the kind of medium in which the 
tubercle bacillus is grown. 2 

Most startling, perhaps, is the fact that Wherry has controlled 
what in biological terms amounts to a change of organism from one 
class into a totally different one. By alterations in the surrounding 
medium he has made certain amebae (familiarly known to you as 
gelatinous masses crawling over a slide) change into free swimming, 
flagellated organisms and back again — a most remarkable piece of 
work. These accomplishments of Wherry 3 mark the most tre- 
mendous variations in a biological sense that have ever been 
accomplished by external means in any group of organisms. 

We turn now to the studies of E. C. Rosenow, who, by special 
methods of isolation and growth, has produced marked variations 
in the members of the streptococcus family. W^hile these studies 
are less striking in a general biological sense, they are most signi- 
ficant in their practical bearings upon the every-day problems of 
health and disease. Some years ago, we recognized as fixed forms 
the old streptococcus pyogenes, the streptococcus longus and the 
streptococcus brevis — all varieties of pus formers; then we had 
listed also the streptococcus erysipelatis, a short chained affair 
occurring in erysipelas cases ; to these was added the streptococcus 
rheumaticus of Poynton and Paine, 4 isolated by them from 
acutely affected rheumatic joints and a little different in morphol- 
ogy and behavior from the other types. To this already long list, 

1 William B. Wherry: Centralbl. f. Bakt.. Parasitenk. u. Infektionskr., 
70, 115 (1913). 

2 William B. Wherry: Jour. Infectious Dis., 13, 114 (1913). 

3 William B. Wherry: Arch. f. Protistenk., 30, 77 (1913). 

4 F. J. Poynton and A. Paine: Lancet, 2, 861 (1900); Brit. Med. Jour., 
1 (1904); Lancet, 1, 1524 (1910); ibid., 2, 1189 (1911). 



APPENDIX 



823 



came ariother streptococcus, which, because it forms green patches 
on media containing blood, is known as the streptococcus viri- 
dans. m As it is commonly obtained from the vegetations of endo- 
carditis, it is also known under the separate heading of strepto- 
coccus endocarditidis. 

One of the important contributions of Rosenow 1 to this whole 
subject has been his demonstration that these various streptococci, 
including the so-called pneumococcus, are related and that it is 
possible to change the typical representative of any one of these 
classes into a totally different one at will. In other words, a 
streptococcus known by one name in one place can, by proper 
cultural methods, be changed into another type. The- important 
thing to be kept in mind is that such changes in culture ground 
occur not alone in the cloistered atmosphere of our laboratories, 
but daily in nature. In other words, an organism like a strepto- 
coccus living an avirulent existence in some neglected point of our 
anatomy, may any day become the progenitor of a highly virulent 
family with mutilating and death-dealing properties, if only its 
surroundings be slightly changed. 

Let it be emphasized that these changes in environment are 
occurring constantly in our bodies, and often in very small areas. 
To give a concrete illustration and one that fits our interests to- 
night, it may be emphasized that the mere pulling of a tooth, with 
the trauma incident thereto, may so change the environment that 
what was a perfectly innocuous type of infection is converted into 
a virulent one, which may kill a patient. And why? Simply 
because the trauma may so affect the circulation through the 
tissues that where once there was plenty of oxygen there is now 
little or none, in consequence of which an organism which pre- 
viously grew as a mere saprophyte now changes entirely and to 
the disaster of its host. 

5. Fundamental Systemic Pathology 

But not only has Rosenow demonstrated how from one type 
of streptococcus others may spring, he has also shown how their 
pathological effects are in essence all produced in the same fashion. 
Nearly all these systemic effects, by whatever name we are going 
to call them later, are due to the fact that the organisms involved 

*E. C. Rosenow: Jour. Infectious Dis., 7, 410 (1910); ibid., 14, 1 (1914). 



524 



(EDEMA AND NEPHRITIS 



get into the general blood stream and while floating in this get 
caught somewhere in the smallest capillaries, supplying different 
portions of our bodies. And. depending upon the particular 
"affinities" of the organism and the location of the capillaries in 
which they are caught, these infections give rise to a whole series 
of different clinical manifestations to which very different clinical 
names have been, and are, attached. In other words, following 
their entrance into the blood stream from any focus whatsoever 
these micro-organisms ultimately give rise to the phenomena of 
infectious embohsm. Only, depending upon the organ struck (in 
its turn, but the expression of accident and the particular type of 
organism involved), we get totally different clinical manifesta- 
tions. Unless as doctors we see the whole patient and under- 
stand what has been and is happening, we can do little to help, 
even though we send for half a dozen specialists to reach each of 
the organs that may be involved. We do not need the specialists 
half so much as one man who will find for us the open door 
through which the infection has been or is entering, and from 
which pathogenic organisms are being sown broadcast into 
different organs. 

After an infection has broken into the blood stream, where may 
the organism localize, and by what clinical name is the localization 
likely to be designated? 

The infection may localize in the heart valves. We used to be 
taught that to produce a valvular endocarditis bacteria floating in 
the general blood stream reached the valves, stuck fast to them and 
then produced the set of inflammatory changes which we call 
endocarditis, and which clinically, give rise to the signs and 
symptoms that some call valvular heart disease. Rosexow 1 
has shown that this notion is wrong. As you know, the heart 
valves themselves have practically no blood vessels in them. 
These run in the body of the heart muscle; and at the places where 
the valves are located the capillaries simply loop and dip into the 
fixed bases of the valves. It is the bacteria floating in the blood 
passing through these capillaries at the base of the valves and 
arrested here that give rise to the original lesion in valvular endo- 
carditis. In this locality the oxygen is not plentiful and so the 
bacteria are likely to develop virulent characteristics which orig- 
inally they may not have had at all. The endocarditis thus started 

l E. C. Rosexow: Jour. Infectious Bis., 7, 410 (1910). 



APPENDIX 



825 



at the base of the valve may gradually involve all of it and finally, 
perhaps, destroy it. 

Just as the micro-organisms floating in the blood may localize 
in the tiny end arteries of a heart valve, they may also come to 
rest in a muscle. 1 The usual spot chosen is where muscle joins 
tendon, for it is here that the circulation is least perfect. Since 
this is synonymous with the least adequate supply of oxygen, it is 
not surprising that here the micro-organisms do their greatest 
mischief. What has been described is the mechanism by which 
muscular rheumatism is produced. Incidentally it also becomes 
clear why rheumatic pains and the tenderest points in this disease 
are located so frequently not in the bellies of the skeletal muscles, 
but at the junction points between muscles and tendons. 

The same changes that appear in skeletal muscle may appear in 
heart muscle. Through the described embolic infection we obtain 
an understanding of the origin of many types of myocardial disease. 

As you know, the linings of joints are also supplied with end 
arteries. They penetrate the synovial membranes and make a 
loop in them. Bacteria may localize in these loops and when this 
is followed by the ordinary inflammatory and proliferative changes 
characteristic of such infection, they give rise to small destructive 
lesions. Briefly put, small infarcts are produced. Usually they 
are anemic, but if bleeding occurs the infarcts become hemorrhagic 
in type. In either case, a destruction of the involved area is 
common. When these things happen we have before us the 
fundamental pathology of a so-called joint rheumatism. If the 
process occurs like a bolt from the blue we call it acute articular 
rheumatism. When it is less acute, it becomes chronic articular 
rheumatism. If it is very slow in its progress and involves not 
only the tissues of the joint itself, but also those about it, and we 
have in consequence in close proximity evidences of an atrophic 
and a hypertrophic type of inflammatory change, we call it 
arthritis deformans. Let me add that, in my opinion, many such 
cases are also called gout. 

These infectious embolic processes may occur also in the blood 
vessels of the skin. This marks the origin of many different types 
of skin eruption. One type that Rosenow has been able to repro- 
duce in animals by injecting certain streptococcus strains is the 
so-called herpes zoster; another erythema nodosum. What 
iE. C. Rosenow: Jour. Am. Med. Assoc., 60, 1223 (1913). 



S26 



(EDEMA AND NEPHRITIS 



tyrants words are ! How often have not patients come to us, told 
us that they had red and swollen patches somewhere about their 
persons, and we have sent them away satisfied after translating 
what they told us into Greek and Latin! 

But not only may micro-organisms circulating in the blood 
localize in the heart, in the muscles, in the joints or in the skin, 
they may do this in the capillaries of the kidney. 1 When this 
occurs, it marks the origin of certain types of nephritis. These 
are commonly called Bright' s disease, though this name ought 
really to be reserved for those kidney changes which are associated 
with arteriosclerosis. If, however, every circumstance that yields 
albumin and casts in the urine is to be called by his name then a 
streptococcus, staphylococcus and many another type of infection 
of the blood stream constitutes one of the possible ways of getting 
Bright's disease. The infectious emboli commonly locate in the 
glomeruli (glomerular nephritis) but they may also come to rest in 
the capillary beds about the convoluted and straight tubules 
(tubular nephritis).- In consequence of the tiny infarcts thus 
produced, spot after spot in the kidney is eaten away. As the 
spots die, albumin and casts appear in the urine. The amount of 
such spotty involvement may, of course, be very general and occur 
very acutely; or it may be very local and slow-going, but never- 
theless progressive in type. Depending upon which prevails we 
have either an acute or a more lasting, chronic, type of nephritis. 

As already indicated, it is after a primary involvement of the 
blood stream with micro-organisms from what may be by itself 
an insignificant lesion that the lungs may become the seat of a 
localized infection, not only in the striking form of lobar pneu- 
monia, but also in the patchy form of lobular pneumonia. And 
these pulmonary infections may be decidedly acute in type, as is so 
commonly the case, or chronic. 

To this already long list of clinical entities, behind which He as 
we now know embolic infections of various kinds (particularly 
with the streptococcus), there must be added some types of thyroid 
disease. Many of these are really infections of the thyroid gland, 
secondary to a blood stream infection originating in some neglected 
focus elsewhere in the body, as in the teeth. The first time this 

*E. R. Le Count and Lelia Jackson: Jout. Infectious Dis., 15, 389 
(1914); George F. Dick and Gladys R. Dick: Jout. Am. Med. Assoc., 
65; 6 (1915). 



APPENDIX 



827 



was told me, I confess that my confidence in the world's sanity 
was shaken a little. Had not everybody taught us that hyperthy- 
roidism was "metabolie," " idiopathic," "physiological" and all 
that sort of thing — fine words with which to stupefy us and keep 
us stupid? 

The gospel of infection was preached to me by Rollin T. 
Woodyatt, 1 who called my attention to the practically constant 
association of " goiter" in patients with mouth infection. In one 
morning, he showed me five patients with typical signs of hyper- 
thyroidism (tremor, cardiac attacks, eye signs, etc.) in every one 
of whom there was well-marked infection about the teeth. With 
my lesson learned it was no trick in the next two days to find three 
goiter cases among some patients of my own, and to observe that 
all had dirty mouths. To these clinical observations, Rosenow 2 
has added experimental ones. He has isolated streptococci from 
human thyroid victims which, when injected into dogs, produce 
the signs of hyperthyroidism. 

Whenever new light is found it is of interest to look back and 
see who in the army of the past saw best with the candles that were 
once supreme. The French clinicians frequently emphasized and 
commented upon the many similarities between the signs and 
symptoms of hyperthyroidism and those of acute rheumatism. 
In acute rheumatism there is a tendency to sweat, a loss of flesh, 
a tremor and a hyperirritability of the central nervous system, 
which are also, as you see, the signs of hyperthyroidism. Last 
summer while going through the library in an idle moment, I took 
down Graves' monograph on the disease which bears his name. 
The clinical details of his first case show this to have been one of 
hyperthyroidism in a woman convalescent from acute rheumatism. 
But acute rheumatism is now but the clinical name for a strepto- 
coccus infection of a certain type. 

But not only has it been possible in the instances thus far 
cited to work out clinically the connection between recognized 
bedside pictures and certain infections, to isolate the organisms 
concerned, and with them, to reproduce in animals the clinical 
pictures from which the organisms were taken originally, but it 
has also proved possible to do this in the case of gastric and duodenal 

1 Rollin T. Woodyatt: Personal communication (1914); see also 
Frank Billings: Jour. Am. Med. Assoc., 63, 899 (1914). 
2 E. C. Rosenow: Personal communication (1914). 



828 



(EDEMA AND NEPHRITIS 



ulcer, 1 cholecystitis with stone, 2 and appendicitis? In other words, 
gastric and duodenal ulcer is the product of an infectious embolism 
involving a larger or smaller patch of the mucous membrane in 
stomach or duodenum. The same is true of cholecystitis. Rose- 
now has isolated from the walls of infected gall bladders and from 
gall stones, strains of streptococci which, when injected into the 
circulation, produce a typical cholecystitis, in the course of which 
tiny gall stones may be seen to begin their development upon the 
surface of the inflamed mucous membrane lining the gall bladder. 
It is a fact of great interest and one in keeping with the general 
idea of the embolic nature of these infections, that such chole- 
cystitis cannot be produced by injecting the streptococci into the 
portal circulation, but only by injecting them into the systemic. 
Similar statements may be made regarding appendicitis. Organ- 
isms isolated from the walls of infected appendices will on injec- 
tion into the general blood stream, reproduce the disease. It is 
certainly remarkable that we get appendicitis, on the best evidence 
now available, not through an infection which travels from the 
bowel, for example, into the lumen of the appendix, but from 
micro-organisms circulating in the arterial blood which have 
gotten into this from some distant focus of infection. 

Once we .get these things clearly in mind, it becomes evident 
how entirely inadequate is the mere diagnosis of stomach ulcer, 
of gall bladder disease, of gall stones, of appendicitis even. True, 
these are local manifestations and such as fill by their acuity and 
immediate dangers our entire consciousness, yet, if we remember 
their infectious origin and that this infection got in somewhere, 
how important becomes the problem of discovering where this 
somewhere is! 

To these observations needs now to be added one by William 
B. Wherry 4 which is destined to play an enormous role in our 
future concepts of disease. Wherry has shown that many patients 
suffering from local infections, as about the teeth, get and have 
periodic sowings of bacteria into their blood streams and, appar- 
ently, without developing therefrom any localizing symptoms whatso- 

X E. C. Rosenow: Jour. Infectious Dis., 19, 333 (1916). 
2 E. C. Rosenow: Personal communication (1915); Jour. Infectious Dis., 
19, 527 (1916). 

3 E. C. Rosenow: Jour. Infectious Dis., 16, 240 (1915); ibid., 18, 283 
(1916). 

4 William B. Wherry: Personal communication (1914). 



APPENDIX 



829 



ever. It will be interesting to discover how many of the down- 
and-outers and bums that frequent our city institutions are really 
the victims of such infection, and how many are constitutionally 
worthless. Our hearts should not bleed too easily for the really 
unfit, but I confess to being moved by Petri plates showing scores 
of colonies of the streptococcus family, cultured from the general 
blood stream of patients, who, on careful clinical examination, 
show nothing but bad teeth and sore gums. Let me emphasize 
that many of the patients studied by Wherky were not bedridden, 
and were in the hospital for minor ailments. Many would be 
regarded as mere loafers; most were "unfit" from the standpoint 
of industry. As a matter of fact, they were ill. This type of 
infection is unquestionably common beyond anything we estimate 
at the present minute. It is responsible I think for much that is 
called "autointoxication," "migraine," "dumb gout" and is the 
real cause of many an anemia. Whence come the pasty-faced 
individuals that fill our cities? Many, if not all, are the victims 
of low-grade systemic infections of a very chronic type. 

The world is full of these people who are not overly well. If 
they are over forty their infirmities are commonly laid to the 
menopause, or to oncoming or established "old age" — things 
which, of course, express nothing more clearly than our ignorance. 
To assign things to old age explains nothing; we need then to ex- 
plain old age. And here much light is going to come to us soon. 
Conservatively, I think, half the things that we to-day attribute 
to old age are really the things that make us old. As has so 
frequently happened in medicine, we have gotten cause and effect 
hindside to. Is not arteriosclerosis, for example — or, as I prefer to 
call it, vascular disease — caused by old age? Were it, then why 
will so many of the really aged persist in carrying soft and 
unscarred arteries into the grave ; and why, on the other hand, will 
some men in their twenties, some in their thirties, and great crowds 
in their forties, begin to show the evidences of disintegrating cir- 
culatory systems? Is it not more probable that the bad system of 
pipes determines the premature old age, and not the other way 
about? If this seems reasonable, then whence come the vascular 
changes? Whenever we are ignorant of the etiology of disease, 
particularly chronic disease, we lay it at the door of man's vices. 
And this has happened for arteriosclerosis as for other obscure 
things in medicine. The only trouble is that on looking about, 



830 



(EDEMA AND NEPHRITIS 



one observes the most virtuous dying of this thing. The worst 
arteriosclerotic I ever saw was a middle-aged, well-to-do, indus- 
trious farmer, who worked moderately every day in the California 
sunshine, who used no coffee, tobacco or spirits, and whose personal 
life was so exemplary that people of his valley called him "Ernest 
the Good." In other words, there are people who do not overwork 
or overworry, who avoid all foods that are worth eating, who never 
use coffee but drink its horrible substitutes, and yet all this gets 
them nothing in the way of freedom from vascular disease. Please 
understand me correctly in this matter. I am not maintaining that 
excesses in some of these directions may not be bad for the indi- 
vidual who has vascular disease. I only want to emphasize that 
there is no evidence at hand to show they caused it. 

The reason I say this so emphatically is because this old guard 
of alcohol, tobacco, coffee, lead poisoning, hard work, meat diets, 
etc., all represent general types of intoxication, in other words, 
they represent intoxication with a soluble poison circulating 
through an organ. But we do not know any such soluble poisons, 
which, when experimentally or otherwise introduced into an organ, 
will involve only parts thereof. When arsenic, or lead, or phos- 
phorus, circulates through a kidne3 r , a liver or a heart, it affects 
the whole quite uniformly. This holds true for the blood vessels, 
too. A soluble poison like a dilute alcohol cannot circulate hour 
after hour through the blood vessels and only injure patches in 
them. Yet, vascular disease (arteriosclerosis) is a patchy disease 
and no matter how advanced, is never seen to have involved all 
portions of the blood vessels. The patches of vascular disease as 
seen in the larger blood vessels really begin in the areas about the 
vasavasorum. In other words, vascular disease begins in, and is 
essentially a disease of, the smallest blood vessels. When it 
attacks the large blood vessels, it really does so only indirectly by 
affecting the small blood vessels which supply the coats of the 
large with nutriment. 1 

We have known for many years that in an enormous propor- 
tion of the arteriosclerotics (in something like 60 per cent of them 
according to certain authors) an organism is responsible for these 
focal changes in the blood vessels, namely, the treponema (spiro- 
chete) of syphilis. The essential changes are again those of 
infectious embolism, involving the vasavasorum. In the remain- 

1 See page 634. 



APPENDIX 



831 



ing 40 per cent (and probably mixed in as secondary invaders 
with many so-called syphilitic ones), we will unquestionably find 
other organisms constituting the emboli from which follow the 
pathological consequences that yield us ultimately the picture 
which, pathologically, we call vascular disease, and clinically, 
arteriosclerosis, or what you will. 1 The infectious embolism is 
again followed by infarction, by partial attempts at regeneration, 
by more definite evidences of degeneration, the whole capped, 
maybe, by a deposition of calcium salts. And following these 
changes in the blood vessels, as they involve different organs, we 
get that whole troupe of " diseases" sa likely to fill our later days. 
There may be hemorrhages into a vital organ like the brain or 
medulla; or a slower shutting off of the blood supply with mental 
deterioration, stupor, coma and death; or portions of the kidney 
may gradually die, giving us a chronic Bright's disease; or the 
changes may involve the heart and we die of a myocardial degen- 
eration; and so on ad infinitum, just depending upon where in our 
bodies this blood vessel disease shows its hand most conspicuously. 

I have given you now a very long list of " diseases " at the causes 
of which we could only guess a few years ago, but which to-day we 
know definitely to be due to infection. The matter is no longer 
one of opinion or hypothesis, but of fact. But to accept this, if 
it has not already done so, must change our whole point of view in 
practice, for the bulk of medical practice is made up of the very 
diseases that I have listed for you. Evidently, the time is past 
when we may rest satisfied with the mere diagnosis and 
treatment of rheumatism, gastric ulcer, vascular disease. 
Exactly as in diphtheria, scarlet fever, erysipelas we must 
not only meet the obvious problem, but trace it to its source, 
to the end that our patient may not again become the 
victim of a like attack, or a menace to those near him. In all 
these patients we must work backwards, and discover the original 
point of entrance of the infection. What good does it do to treat 
an acute rheumatism if after we have nursed the patient through 
one attack he is left liable to a second, third and fourth? Because 
fortunate once, it does not mean that he will win always. And 
what is true of rheumatism is true of endocarditis, of gastric ulcer, 
of appendicitis, of gall bladder infection and the rest of the cate- 

^ee in this connection the vascular changes noted in, rabbits by T. B. 
Hartzell and A. T. Henrici: Jour. Am. Med. Assoc., 64, 1055 (1915), 
after the intravenous injection of streptococci isolated from alveolar abscesses. 



832 



(EDEMA AND NEPHRITIS 



gory. As long as the patient continues to carry about in him his 
original source of infection, his symptoms may recur again and 
again. 

6. Points of Entrance for Systemic Infection 

This explains why it is so necessary to discover the original 
source or sources. And where, pray, are they most likely to be 
found? The tonsils are among the most conspicuous lodging 
houses for these infectious organisms. They have, of course, long 
been the subject of uplift work by the nose and throat surgeons. 
I confess to having nryself laughed at them but many times since 
have I asked for forgiveness. As a medical man, the appeal to 
surgery has to me much of the cry of defeat about it, but the most 
radical tonsillectomist is a conservative compared with me now. 
I have insisted on the removal of many a tonsil which some of 
my throat colleagues said might stay. No- tonsil from which pus 
may be squeezed is above suspicion, and let me add that I have 
squeezed pus from not a few tonsils in which some of my nose and 
throat friends said there was none. I am going to apply this 
lesson to the dentists in a minute. Let me emphasize that in 
patients with the constitutional findings which we are discussing, 
especially when progressive in type, such foci of infection must 
be found. The negative reports of half a dozen specialists means 
nothing in these matters. Only positive findings count. I have 
seen Rosenow find pus in tonsils where throat men swore there 
was none. He has now equipped himself with dental tools and 
laryngologist's instruments with which he gets pus out of teeth 
where dentists did not see any, and out of sinuses and throats 
where laryngologists missed it. And the pus thus obtained is 
proved the source of the various constitutional signs of which 
the patients complain by injection into animals which develop the 
same pathological pictures as shown by the patients. 

You see what this means. In the too intense contemplation 
of our particular fields of specialism, we are likely to lose sight of 
the whole man; and then it takes a genius like Frank Billings 
or Rosenow to put us on our feet again, and to teach us that a 
plain doctor is more important to the patient than a whole group 
of specialists. 

What has been said of the tonsils holds also for the nose, for the 
sinuses of the head, for the ears. In women we must consider the 



APPENDIX 



833 



pelvis as a focus for infection, and in men, the genito-urinary 
tract. Infected hemorrhoids are always to be looked for; and 
infected points on hands and feet, as ingrowing toe nails. 

This ends the list of the common places in which infections are 
harbored until we reach our own specialty, that of the teeth. 1 
When the tonsils are out (really out), as is commonly the case in 
young adults, when there is no infection in the ears or sinuses, 
when there is no genito-urinary infection, the problem usually 
comes right down to the dentist. Personally, I think that this 
matter of infection about the teeth, judged by its established and 
potential consequences, is to-day the biggest one problem in 
medicine. 

As I have emphasized previously, the gospel of the association 
between infections of the teeth and these .systemic disturbances, 
has been preached off and on for many years and by not a few 
dentists. What gives force to these later day arguments is that 
proof has ceased to rest merely upon good clinical observation and 
medical judgment. There is now scientific proof of the truth of 
what these men have so long maintained. Organisms have been 
isolated from the systemic foci of infection — from joints, muscles, 
gall bladders, gastro-duodenal ulcers, appendices — and with these 
organisms the specific disturbances have seen reproduced in 
animals. And more, the organisms responsible for such systemic 
disease have been isolated from infected teeth (and other foci of 
infections), and with these the same constitutional disturbances as 
exhibited by the patient, such as muscular and joint rheumatism, 
gastro-duodenal ulcers, gall bladder infection, etc., have been 
produced in animals. The chain of evidence is, in other words 
everywhere complete. 

As practical men of everyday medicine we are most interested, 
however, in the clinical evidence for the correctness of these 
things. I am not going to weary you with a recitation of case 

1 The intestinal tract (exclusive of chronic gall bladder and appendix 
infections) is undoubtedly a source for occasional or periodic invasions of 
the blood stream and so of the whole man. There is much clinical evidence 
for this and some bacteriological and surgical. I omit its discussion intention- 
ally because its importance is not yet proved in the conclusive fashion in which 
are the others taken up. Moreover, to relegate infection to the intestinal 
tract is to put it largely beyond therapeutic reach and thus to make us 
content with the maintained invalidism of a patient. To ignore the intes- 
tinal tract is to encourage more careful search of the superficial and thera- 
peutically more tangible regions of anatomy. 



834 



(EDEMA AND NEPHRITIS 



histories, but the improvement in patients when the first source of 
their troubles is discovered and removed is really most remarkable. 
Most illuminating illustrations of this kind were first detailed 
by the creator of this chapter of the focal infections in modern 
medicine, namely, Frank Billings. 1 Since then such reports have 
multiplied to an incalculable number. Of course there have been 
those who have denied the truth of Billings' fundamental teach- 
ings and the improvement in patients after attention to foci of 
infection. But one does not need long to be a worker in this field 
to recognize that such judgment is a more damning index to the 
skill of the critics than to the truth of Billings' teachings. I 
doubt not that the future will turn to Billings' work and see 
in its practical results a greater release for man from his suffer- 
ings than in any other medical work that I know of in the past 
quarter century. 



7. Illustrative Case Reports 

Among the patients that I have seen, I remember one of my 
surgical friends who had lost all his teeth except five lowers. He 
wore an upper and lower plate. He used to have his faithful 
five " treated" by one of the best prophylactic dentists that I 
know, and he went regularly and conscientiously to have done 
whatever was ordered. After a series of minor attacks, associated 
with great pain, he developed a weakness of the right arm. Being 
a surgeon he was practically robbed of his best instrument. The 
pain and weakness was due to pressure upon the brachial 
plexus, occasioned in its turn, as the x-ray showed, by a thickening 
of the bony parts in the vertebrae of the neck. For three years he 
tolerated his incapacitated state, always in pain and constitution- 
ally half ill. Then the five teeth were pulled. In a few weeks he 
got perfectly well and has remained so. The long preceding 
history and his maintained freedom from any of the old signs and 
symptoms makes it impossible to deny the definite connection 
between his teeth and his arm affection. 

A year ago I had a man who, for two years, had been carried 

1 Frank Billings: Arch. Int. Med., 4. 409 (1909); ibid., 9, 484 (1912); 
Jour. Am. Med. Assoc., 61, 819 (1913); Illinois Med. Jour., 25, 11 (1914); 
Jour. Am. Med. Assoc., 63, 899 (1914). 



APPENDIX 



835 



from one sanatorium to another, because of a cardiac arrythmia. 
He would drop certain heart beats completely. I guessed that the 
disturbance was due to an involvement of the so-called His bundle 
of the heart, and believed that a relatively small lesion might be 
responsible for it. At present, one can hardly imagine such a 
local involvement as due to anything but a focus of infection. It 
was incumbent, in consequence, to look for a point of entrance. 
I discovered as such possibilities a badly placed and infected bridge 
and two lower teeth that were running pus. I advised the patient 
to have the bridge taken off and the two teeth pulled. The man 
recovered completely in two weeks. 

Last year also I saw a man whose story illustrates the many 
roles that a streptococcus infection may play. He came to me 
because he had albumin and casts in the urine. He had been told 
that he had Bright's disease, and that his future was not an encour- 
aging one. I learned upon examining him that he had also had 
an infection of the gall bladder in the past year, and this had been 
operated upon and drained. He had also had an acute appen- 
dicitis during this year, though not at the same time as his gall 
bladder infection but following it. For this he had also undergone 
an abdominal operation. After recovering from it he developed 
an abscess in the deep tissues surrounding a shoulder joint. When 
I examined him he still had the plain evidences of a myositis in 
various muscles at the points of union of muscle with tendon and 
he told me that his joints would occasionally swell. Except for a 
trace of albumin, all these signs and symptoms disappeared in a 
few weeks after six badly infected teeth were removed. 

It is hard, of course, to consider as of any importance a dirty 
mouth and bad teeth, when we are face to face with the "acute 
surgical abdomen," or when we are damning a man's future with 
the prospects of " Bright's disease," but does not this simple and 
so common tale teach us that we ought to? 

I want to be correctly understood about these clinical histories 
which might be multiplied indefinitely, as I have detailed them to 
you. They are given to illustrate how clinical experience will 
verify, day after day, the intimate association that exists between 
focal infections and systemic disease. They are not cited to show 
how the pulling of teeth "cures" systemic disease, even when due 
to the organisms located in the region of the extracted teeth. 
I content myself by assuring my patients that if they will 



836 



(EDEMA AND NEPHRITIS 



have their foci of infection removed they will grow no worse. It is 
a fact, however, that a removal of the original source or sources of 
the infection leads to an entire clearing up of all systemic evidences 
of disease in a large number of instances, improves others tre- 
mendously and leaves but very few patients without some benefit. 
All this is, of course, most remarkable, for the S3 r stemic disturbances 
of which the patients complain are due to the localization of micro- 
organisms in the distant organs and these are not touched when an 
original focus occurring in a tooth, a tonsil or elsewhere is removed. 
The improvement must be obtained in some indirect way. Of 
course, we stop by. our surgery the periodic seeding of micro-organ- 
isms into the blood and so prevent new attacks and the progress of 
the disease. But apparently, we help in other ways too. By 
removing some of the infection the patient has, temporarily at 
least, an overplus of his antibodies, or the local reaction following 
extraction, etc., may stimulate a greater production of such. 1 
And these give the patient a boost which helps him to overcome 
the infection wherever else it may be in his body. 

If this close relation between infected teeth and systemic 
disease is granted, then the teeth assume not only from a curative, 
but still more definitely from a prophylactic point of view, an 
importance that is not ordinarily accorded them. Not that many 
a dentist and many of you here to-night have not always recognized 
and met this important problem. But if my experience in the 
matter is any guide, then a majority of the dental profession is 
not yet alive to the whole problem, and many things are still done 
by dentists of a type, which, far from relieving these mouth infec- 
tions, actually bring them about or favor their development once 
they are established. It is for this reason that I am going to 
venture upon the dangerous ground of saying what I think ought 
to be done about some of these infected teeth, or rather, what 
should be done in order that our teeth may never become the 
menaces to our general health that they now are. 

8. Remarks on Some Dental Procedures 

The reason that I dare to speak upon this subject is because I 
think that the principles of science do not change just because the 

!See Clyde Brooks: Science, 49, 196 (1919); New York Med. Jour., 
109, 452 (1919). 



APPENDIX 



837 



things to which we apply them have names different from those 
in another field for which we know these principles to work. In 
other words, the fundamental principles of general surgery cannot 
be abrogated just because we choose as the special field for surgical 
endeavor the mouth and teeth. That may sound like cant to 
-you, but from conversations that I have had with some of my 
dentist friends, they seem to think that the teeth belong in a class 
by themselves, and that they have nothing whatever to do with 
the other things that we have in our bodies. 

Now, plainly put, the teeth are simply thirty-two bones in 
thirty-two joints. Even without adding to these the other bones 
and joints in the head and neck upon which the surgical dentist 
frequently operates, he has here almost as many joints in point of 
numbers as an orthopedist is asked to work upon. And dentistry 
is to me, when rightly viewed, just as great a profession as is this 
other division of medical practice that we call orthopedic surgery. 
But all of us will agree that we have never demanded of the den- 
tist (as we have every right to do) the training and the skill of an 
orthopedic surgeon, and certainly there is a frightful gap between 
the principles of surgery as employed by the general surgeon or 
the orthopedist and these same principles as brought into play 
in the treatment of teeth. Yet why should such a difference be 
tolerated, for the principles of which I shall speak are those which 
cover bone and joint surgery; and the pathological states referred to 
are, in plain English, those of infection, — those of osteitis, osteo- 
myelitis, arthritis and the problem of the fate of sterile or infected 
sequestra. 1 

The first thing that some dentists — please do not think that I 
say this of all — the primary thing that some dentists forget is 
that the tooth is first, last and all the time a living structure. The 
reason I emphasize this is because dentists often work upon teeth 
and use things on them which they would not think of applying 
to the skin, to the peritoneum, or to the inside of a joint. Yet 
their effect on both is the same. Rough instrumentation is not 

1 1 have during the past several years seen many patients in association 
with Gustav Eckstein, Jr., whose cooperation I acknowledge with a lively 
sense of gratitude. Had it not been for his enduring patience, his operative 
skill and his sound knowledge of pathology the lessons we have learned in 
common would have been fewer and the suggestions regarding dental 
surgery and its possibilities as reaffirmed in these pages (1920) less cate- 
gorical. 



838 



(EDEMA AND NEPHRITIS 



without its by-effects, a hot drill cooks a tooth like a softer 
tissue, and antiseptics, especially when concentrated, 'kill teeth 
as rapidly as micro-organisms. 

I ought not to have to say that many dentists ignore the first 
principles of aseptic surgery but certain it is that they do. The 
problem is not altogether easy, for most dental procedures are 
necessary upon teeth already frankly infected. But where work 
must be done upon such the need for initially clean instruments, 
for their frequent change and for eternal care not to transmit 
infected material from one spot to another is all the more obvious. 

For the reasons already emphasized there is not much gained 
when the dental surgeon tries to clean up an old infection or tries 
to cover the defects of his technic by the use of antiseptics. We 
have gone through this same stage in general surgery. I am 
serious when I say that one of the reasons why dentists generally 
have gotten the good results they have is because they have largely 
worked without any regard to antiseptic measures. Under such 
circumstances their grindings, etc., usually occur in live teeth, and 
as long as they are alive, they are hard to infect. This is but an 
application to the teeth of a surgical truth not yet fully grasped 
by even the general surgeons. The difference in susceptibility to 
infection before and after the death of cells is easily proved. 
When, for example, any open wound that is covered with healthy 
granulations is sown with bacteria (such as one of the pus formers, 
including the streptococcus), the chances of getting an infection 
are extremely small. But if at the same time that the bacteria are 
sown, a piece of gauze is lightly dragged over the wound so as to 
crush the living and growing cells constituting the granulations, 
pus develops within a few hours. In other words, as soon as a 
tissue is killed, its liability to infection is great, and this is true, 
whether the tissue is called skin, peritoneum or tooth. And yet, 
as I shall point out in a moment, many dentists kill a tooth in any 
of their several dental procedures and still think that they have 
done no serious thing. These considerations explain why in all 
surgery a gentle touch with soap and water cleanliness may and 
frequently does mean more for the patient than the most elaborate 
antiseptic technic applied by clumsy hands. Obviously, if the 
greatest resistance to infection is offered by the living tooth itself 
then the patient, first, needs to protect his heritage; while we, for 
our parts, must aid him by keeping off his teeth all antiseptics 



APPENDIX 



839 



likely to kill his living tooth cells and all the dental procedures 
which, like abusive cleansing methods and badly applied bands, 
clasps, crowns and bridges, etc., more or less promptly do his 
teeth to death. 

But not only must we protect the tooth from such external 
injury (with its subsequent disastrous liability to infection) but 
still greater caution is necessary when working within a tooth. 
Many dentists " devitalize," much too readily. To devitalize 
means, of course, to rob a tooth of its life, and yet when I have 
discussed this question with dentists they have generally talked 
about the procedure as if it meant merely a robbing of the tooth of 
its nerve supply. There is a fundamental error in this view. 
When, on his own admission, the dentist thus robs a tooth of its 
nerve supply, he robs it at the same time of its central, nutrient 
artery, which, when not done deliberately and with a full knov/1- 
edge of the consequences, is little short of a crime. The problem 
is analogous to the cutting off of the nutrient artery to one of the 
long bones, the inevitable result of which is a death of the supplied 
area and the formation of a sequestrum. Applied to the tooth, 
devitalization means the same thing, — a death of a part or all of the 
inside of the tooth and the conversion of this into a sequestrum. And 
the future of that tooth is the future of a sequestrum anywhere 
else in the body. I know that some of you will protest that this is 
not so and insist that the tooth still gets a second blood supply 
through its periosteum which may keep it alive. In the first 
place, such a statement is not true; secondly, were it, then a lot 
of the things that are done afterwards to such a devitalized tooth 
are of a character to assure absolutely a suspension of any nourish- 
ment that is supposed to be brought, thus vicariously through 
the periosteum. In other words, some dentists after killing the 
inside of the tooth, later see to it that the periosteum is killed also. 
After that the whole tooth is dead. 

Now, why do I say these things? Simply because some of the 
commonest dental procedures, as the placing of a gold crown, 
does this very thing. It is the accepted procedure with many to 
devitalize the pulp before placing a crown. This kills the inside 
of the tooth, as I have already said. To get a good fit for the 
crown, the convex sides of the projecting portions of the tooth 
are ground off, which means a killing of many of the living cells 
in this portion of the tooth. It is generally accepted, I believe, 



OEDEMA AXD NEPHRITIS 



that the crown must fit snugly about the neck of the tooth, pro- 
jecting to or somewhat under the gum line. All dentists agree that 
if a snug fit is not secured, infection is bound to occur. Let me 
insist that infection and trouble are just as certain if the crown does 
fit snugly. And when to secure a perfect fit, or to make good a 
tooth defect extending under the gum line, the dentist first strips 
back the gum or forces the crown deeper, what, but disaster can be 
expected? Under the gold, always when badly placed, and nearly 
always even when well placed we have dead bone and injured 
peridental tissues (periosteuni and synovial membrane) and, as a 
corollary, infection. If you do not believe this, just examine such 
crowns yourselves. In the course of routine physical examina- 
tions, one can look at the teeth of all his patients week after week 
and never find a gold-capped tooth that does not run pus. I con- 
fess to having been shocked, when, on referring these patients 
back to then dentists, they have returned to me with the state- 
ment that then- dentists declared their teeth in good order. More 
than one dentist has written me that the pus I observed was a 
" normal secretion'' from the gums. 

The important tiling in all this is that every such crowned tooth 
and, of course, every other infected tooth, whether it is crowned or 
not, constitutes a point of infection from which any of the serious 
things we have previously discussed may result. Mind you, I 
do not say will result — Nature is very kind to us — but may. 
The day is coming, I think, and very soon, when a gold crown 
placed as I have described will not be put on any more. And 
when such gold crowns go, many another now popular piece of 
dental engineering which builds on such crowns will also pass out. 

9. Some Suggestions 

Since I condemn in this wholesale fashion, you will perhaps 
retort by asking me what I think ought to be done. As in dentistry 
I am entirely out of my field, I may perhaps step boldly where 
angels have feared to tread. 

Fust, of course, comes the old story of prophylaxis. I know 
how much the dentists have done here and yet still more must be 
done. I confess to large discouragement regarding our ability to 
handle teeth conservatively once they are extensively infected. 
Hence, my repetition of your own estimable teachings. Every- 
thing possible must be done to keep the teeth from decaying and 



APPENDIX 



841 



the peridental tissues from becoming infected. And how is this 
to be accomplished? 

The health of an organ is best preserved by its proper use, 
wherefore the injunction to use the teeth and use them hard. 
While their employment as nut crackers is hardly to be recom- 
mended, this is a safer extreme than that other which finds virtue 
in our now so universal slop diet. The teeth are bones set in 
joints; and bones and joints are kept in order by exercise. The 
teeth should be given bread crusts, toast, tough meat, meat rinds 
and vegetables rich in cellulose to reduce to pulp with no external 
aid except the saliva. There has been much written of the bad 
effects upon the stomach of taking fluids with meals. Every 
modern fact proves that the contrary is the case — gastro-intestinal 
secretion, digestion and absorption are all favored by large fluid 
intake. I am guilty of the paradox that fluid with meals is not 
bad for the stomach but very bad for the teeth. If it is to be 
consumed it should be taken between mouthfuls of food — not with 
them. 

To this injunction is to be added that of proper brushing — 
brushing of gums and teeth. A new brush which tends to cut the 
gum because its bristles are cut on the bias may be made safe by 
lightly singeing the bristles with a lighted match. 1 The hardest 
bristles are none too hard and a brush with bristles set to taper 
toward the tip reaches back teeth better than the fancy forms 
expected to get between the teeth. The tooth brush should be 
used dry. Healthy gums and teeth may be brushed up and down — 
if infected, the upper teeth had best be brushed downwards only, 
the lower, upwards only. This massages infected material into 
the cavity of the mouth and not into the bases of infected gum 
pockets.. If a dentifrice is desired dry table salt does well, or 
plain baking soda. Precipitated chalk may be used or milk 
of magnesia. Dissolved in the little saliva which flows as brushing 
is continued, these materials form concentrated (hypertonic) 
neutral or alkaline solutions which tend to dehydrate swollen 
gums thereby making for better circulation through them and 
hence a better opportunity for preserving the healthy or aiding 
in the repair of the diseased gum. Hence, too, the injunction not 
to rinse the mouth too quickly after brushing — allow the salt 
solutions time for action upon the gums. Prepared dentrifices 
1 1 learned this from C. C. Bass and F. M. Johns of New Orleans. 



842 



(EDEMA AND NEPHRITIS 



containing soap, chalk, potassium chlorate or glycerin obviously 
work in similar fashion. The best have little direct germicidal 
power — had they such, they would probably be as dangerous 
as they are strong. 

The day of the dental quack who " cleans teeth free," by way 
of getting what looks to him like a real dental job seems largely 
over. But the honest efforts of the modern practitioner really to 
clean teeth seem also to be largely misapplied. In the first place 
the dentist cannot do through a yearly sitting what a patient cannot 
or will not do for himself twice daily. There are times, no doubt, 
when the dentist may give aid by helping mechanically to remove 
gross deposits like tartar. But this is ticklish business. Assum- 
ing that the dentist will make no gross errors in technic (as by 
canying with dirty instruments the infection from one tooth to 
another) it is still to be remembered that such infectious depots 
cannot be stirred into without possible serious consequences. 
Tartar deposits about the teeth are like the "stone". formations 
elsewhere in the body — and surgeons do not lightly scrape about 
in infected gall bladders, urinary bladders or the interiors of 
calcified rheumatic or " gouty" joints. When the dentist follows 
a tartar deposit below the gum margin and into the peridental 
membrane he is in very fact in an infected joint and mechanical 
procedures in this locality are then of the same importance 
and significance as though carried out in a knee joint. The 
cleansing and keeping clean of the teeth is by itself a significant 
job and when the public demands dental help for its proper pros- 
ecution it must recognize its importance and prove willing to pay 
for it just as readily as it does now for bone and joint surgery 
elsewhere in the body. 

But suppose that in spite of all care, infection and decay has 
gotten a foothold either in the form of a caries involving the pro- 
truding portions of a tooth or as an infection of the peridental 
tissues (pyorrhea). To limit ourselves, temporarily, to the first 
of these problems, it is obvious that we need to grind away the 
affected portions and to fill; and we are going to keep on filling as 
long as we can; and when we cannot fill any more, or such is not 
best, we are going to put in inlays. And when the inlays are so 
large that they will not hold any more, then what? It is common 
to crown, but in my opinion it is far better to follow a surgical 
procedure to which some of my dental friends resort, namely 



APPENDIX 



843 



put in a necessary inlay and then half crown to keep the inlay in 
place. A half crown is the expression of good surgical principle. 
An inlay may even be used if the decay extends to below the gum 
line in a limited portion of the tooth. With the half crown, the 
upper tooth structure does not have to be destroyed, and, maybe 
even with the inlay, no devitalization of the tooth pulp may have 
proved necessary. This avoidance of devitalization is most 
important, for devitalization, because of the reasons already dis- 
cussed, defeats us from the start. 

When the upper half of the tooth is so badly shattered that fill- 
ings, inlays, or inlays with half crowns no longer prove adequate, 
then the jacket crown is to be considered. The important thing 
about the jacket crown is that it does not necessitate devitalization. 
As soon, of course, as a tooth is, or has been killed, the jacket 
crown is largely useless, because the mischief is now done and it 
does not add much to stick on a porcelain crown, for example, 
by the old peg method. But as long as the tooth can be kept 
alive it is our sacred duty to keep it so, wherefore the superior 
merits of the porcelain jacket crown which, well cemented upon the 
healthy root-remains of a tooth, expresses to me the very acme of 
surgical thought, ingenuity and skill. Its expense has been urged 
against it ; but has this ever been an adequate argument in medical 
and surgical practice? Whatever its cost, is it not cheaper than 
gall stones, or appendicitis and a fortnight in the hospital? 

Thus far in our discussion we have assumed that the injury or 
infection of the tooth has not extended through the head in such 
fashion as to make devitalization anything but a matter of choice. 
But often, at least in the light of our present knowledge, devitali- 
zation has to be practiced as a matter of necessity. Are we never 
to devitalize, even under such conditions ? I would say, never 
without a full realization of what the consequences are likely to be. 
The future for a devitalized tooth is, at the best, that of a sterile 
sequestrum; at the worst, that of an infected one. And the 
chances for it being the latter are more than nine to one. Where- 
ever infection and devitalization by nature or man go together 
I am of the opinion that the tooth might as well be sacrificed at 
once. If devitalization is done with intent, the double danger of 
infection and dead bone must ever be carried in mind. Living 
tissues can withstand much infection, and a sterile sequestrum, 
like a sterile foreign body, can be tolerated. An infected seques- 



844 



(EDEMA AND NEPHRITIS 



trum will not, however, stay in a tibia or in a femur; nor will it in a 
tooth, just because the necrotic area is small and we give the bony 
growth a special name. 

Examination of devitalized teeth by clinical methods and by 
x-rays shows lesions in and about them in nearly every case. 
Most of these, and the most dangerous, are hidden from the 
casual eye. They are commonly within the tooth itself or the x-ray 
may show them at the root tips and about these. Moreover, 
not a little of such trouble may have been planted there by the 
dentist. The needle or burr or hair that kills or fishes out a dead 
dental pulp all too often carries micro-organisms into the depths 
of the tooth which may have been harmless enough more 
superficially, but which, sealed in the bottom of a cavity away 
from oxygen, develop pathological properties of no advantage to 
their host. 

These remarks will suffice to show why I lay such small value 
also upon root amputations, arsenic and formalin packs, root 
canal fillings and a dozen other dental projects. Root amputa- 
tions cut off the blood supply to a third, a half or all of a tooth 
leaving the upper tooth structures to wither like flowers whose 
stems have been cut below ground. Antiseptic packs, if they kill 
bacteria, kill as probably live tooth structure. If anything is 
gained it is represented by the choice between an infection in a 
living tissue and the substitution for this — if things come out well — 
of a mummified, necrotic and (possibly) sterile patch. Root 
canal fillings, if improperly made or of improper materials, are 
admittedly purposeless; but they are equally futile when made by 
the genius of a Callahan — they are mere pourings of balsam upon 
the dead. 

How proportionally many are the gross lesions around dead 
roots is shown in an interesting study of radiographs made by 
Thaddeus Hyatt 1 who examined 2800 radiographs. Even of 
the 2 per cent of these with fully filled canals, 25 per cent 
showed destruction. And in a similar study by Gustav Eck- 
stein, Jr. and H. Germann a yet higher proportion were made 
out, namely 75 per cent. The latter compilation shows that it. 
makes little difference, so far as subsequent destruction goes, 
whether canals are perfectly filled or not filled at all. For the 
examination of 1950 radiographs revealed that while 75 per cent 
1 Thaddeus Hyatt: Jour. Nat. Dental Assoc., 4, 594 (1917). 



APPENDIX 



845 



of entirely filled canals entailed bone destruction, only 80 per cent 
of those not at all filled were in the same fix. 

Similar opinion covers the value of crown amputations and the 
future of superimposed restorative portions. Pearly porcelain 
tops, in solitary or in phalanx, pegged into such half dead or dead 
root tips, always when badly coapted and usually when well 
placed, spell ultimate infection with the death, of course, of any- 
thing that may originally have escaped. Such teeth may be the 
joy of wearer and friends, when viewed superficially; but they are 
whited sepulchres hiding a foul basement. 

10. The Foul Breath and the Coated Tongue 

Now that I have used the word "foul," let me interpose a 
few remarks on this whole question of foul mouth, foul breath and 
coated tongue. The authorities, it seems to me, who write on 
these subjects go too far to seek the source of such troubles. I am 
convinced that every such state — barring the few cases we observe 
in the hospital which usually concern the acutely and desperately 
ill — means something wrong locally in the mouth or head, 
usually just mouth, and about equally divided between in- 
fections of the teeth and of the tonsils. The probability that 
the tonsils are at fault is somewhat higher in children than in 
adults, while the opposite is true for the teeth. Neither rule, of 
course, holds absolutely, because even young children have 
badly infected teeth, and many adults, given to holding on to 
everything they can, refuse to part with even desperately infected 
tonsils, because they think that someone may some day discover 
a function for them. I look for, and thus far have not failed 
to find infected teeth, infected tonsils or infected sinuses in every 
ambulatory patient who has a bad breath or a coated tongue. To 
blame these things on the "stomach" or "indigestion," is to say 
nothing at the best and, at the worst, to lull the patient into a 
state of false security about himself. 1 

Perhaps some of you would now like to ask: "And is there not 
a relation between these foul mouths, these infected teeth, and 

1 "It might be well to note here that most of the bacteria about the teeth 
and in the tonsils grow better under anaerobic conditions. An anaerobic 
culture of such a mixed flora, made upon blood or serum agar in the abscence 
of carbohydrates, develops the identical foul odor possessed by a 'bad 
breath. ' " — Wherry. 



846 



(EDEMA AND NEPHRITIS 



the 'metabolic' disturbances and 'constitutional' diseases like 
'gout' and 'rheumatism/ of which these patients complain?" 
The answer very decidedly is: "Yes." Only the teeth did not 
attain their state through the rheumatism and gout 1 but the 
other way about — the infected teeth were the cause of these. 2 
Our discussion seems to have strolled from the fields of pro- 
phylaxis, fillings, inlays and crowns to the less pleasant ones of 
pyorrhea and its several adjectives. Let me add my protest to 
that of many a dentist who insists that the term is not broad 
enough, for the pus in pyorrhea does not always flow. Nothing 
would help more to clarify the whole situation than were we to 
ignore this term entirely and cover the whole story of peridental 
infection by the term dental arthritis. For arthritis is what we 
are dealing with and whatever we hold to be of medical or surgical 
importance in the meeting of the situation must rest upon what we 
hold to be correct medical and surgical practice for an arthritis 
anywhere in the body. The first all-important fact to keep in mind 
in this matter of dental arthritis, no matter how restrictedly or 
broadly the term is used, is its infectious origin. The number of 
infectious organisms that may be or are responsible for it, is, no 
doubt, several; 3 but that it is an infection of the dental and peri- 
dental tissues, that is the fundamental thing. And these infec- 
tions have a beginning. It is then that most can be done to over- 
come them and hence the importance of recognizing the early 
evidences of infection. Every tender gum, every bleeding gum, 
every eroded gum, every tender tooth and the slightest evidences 
of pus formation at the gum line of a single tooth mean something. 
The red, soggy gums of the kitchen help and of the young male 
laborers who abhor a tooth brush are all expressive of infection 
and are the red flags of danger ahead. And the flag is just as red 
and full of meaning when the higher strata of society are attacked. 
The ignorance of the individuals most commonly attacked makes 
reform here look desperately unpromising, but we need not add 

^or remarks on the association of "gout "with foci of infection about 
the teeth, see page 756. 

2 Very rarely the tooth sockets, instead of being the first points of infection 
and the sources of seed to other joints, may be infected metastatically 
through the blood stream (see E. C. Rosexow: Jour. Immunology, 1, 363 
(1916)). I do not stress the point because ; t may lead to even less being 
done to control obvious points of infection in the teeth than is now the case. 

3 C. C. Bass and F. M. Johns: Jour. Am. Med. Assoc., 64, 553 (1915). 



APPENDIX 



847 



to the whole problem by having some of our professional brethren 
say that there is nothing wrong with these mouths. What can be 
done with these peridental infections? The proper use of the teeth 
(even though the procedure is painful), a proper brushing of the 
teeth as already outlined and a careful soaking of the mouth 
structures in hypertonic and alkaline salt solutions helps much. 
Under such circumstances, superficial lesions, at least, can be made 
to heal, albeit, at times, not without a certain amount of recession 
of the gum line and exposure of the dentine. 

But what if the infection is more extensive? Let me confess at 
once to a most discouraging experience in the matter of actual 
results obtained and obtainable in more extensively established 
mouth infections upon which some of my dental colleagues have 
worked and by methods more conservative than extraction. Only 
rarely will an infection that has penetrated deeply along the peri- 
dental tissues, as to the tip of the root, clear up. Where this has 
happened nature points to the principle which the dentist should 
follow in attacking these pus pockets — they^ should be laid open 
to their tips and allowed to drain. The pocket may then clear 
up after a retraction of the gum edges. 

Worst of all are the infections which have burrowed up from 
the root following infection by fair means or foul of the dental pulp 
itself. None of these have I ever observed to clear. 

Nothing is worse for the patient (as witness the commonness 
of rheumatic attacks, herpes zoster, endocarditis or appendix 
attacks after a visit to the dentist) or more wrong in surgical prin- 
ciple than the commonly practiced "scaling" of such infected 
teeth. If the dentist could only remember, whether he be the 
conservative scaler who employs hand tools only or the radical 
who starts out with motor driven vehicles, that what he is doing is 
making hash of an infected joint and that what he is accomplishing 
is a perfect destruction of its lining membrane he would soon stop. 
I confess that after the work of such men I have seen the teeth 
assume a better appearance, the gums a less soggy look and have 
seen loose teeth " tighten up" a bit. All that this means is that a 
series of ankylosed (and functionless) joints have been substituted 
for a series of soggy ones. But even this advantage is small if the 
general condition of the patient does not improve or, as is so com- 
monly the case, new "rheumatic" and "gouty" attacks accompany 
the dental work, or appear in patients who never had them before. 



848 



(EDEMA AXD NEPHRITIS 



I have seen exhibited the usual x-ray plates which show how 
after such scaling new bone is formed and all that sort of thing. 
All this is true, but new bone formation and a little better set to the 
teeth is not all we want. We want freedom from infection. 
Bone formation and plenty of it occurs in all bones and their 
periostei whenever there is an infection of these structures. But 
a surgeon in such cases does not try to see how much of the sepa- 
rated and dead bone he can get to grow fast in his patient. He 
pulls it all out. Nor does he expect the infection to cease until he 
has done this very thing. When we call the dead bone a dead root 
or a devitalized tooth the problem is exactly the same. We need 
to get rid of these and then the infection will usually take care of 
itself. 

In the patient with an established or threatened systemic 
infection, the important thing from his point of view does not 
reside in the question: "Have the teeth been saved and has the 
mouth been made to look better?" but rather is this: "Has the 
focal infection from which the systemic has arisen been gotten out 
of the way?" 

As a last word may I comment upon a remark which is con- 
stantly made to me? Time after time one receives the report 
from a dentist that a tooth for which extraction has been sug- 
gested "is alive." The corollary that one is supposed to draw is 
that because the tooth is alive, it cannot therefore be infected. 
Nothing is more absurd. While dead teeth are more susceptible 
to infection, live teeth of course, can be infected. While a dead 
man putrefies of necessity, even a live one may develop an abscess. 
And the situation is the same for such dead and live teeth. 

11. On Extraction 

My remarks will I trust have served to show you why I think 
the only way out of many present-day dental difnculties is over the 
hard road of extraction. But even extraction when fully justified 
and consented to, needs thought in its execution. If more than 
one or two teeth need to come out it is well to decide at once not 
to extract the necessary group at a single sitting and the whole 
process needs to be surrounded by all the care and precautions 
which are customary in bone and joint surgery anywhere else in 
the body. 



APPENDIX 



849 



Extract one or two teeth at a sitting, especially if they are 
molars, and allow several days to elapse between sittings. In the 
interval fresh granulations cover the sockets and liability to cross 
infection is reduced. The best anesthetic is gas and oxygen; 
next best is the careful use of novocain. Objection to the latter 
is dependent upon the often unavoidable necessity of pushing the 
hypodermic needle into or through infected tissues. The teeth 
should be removed with the least possible trauma to mandibles or 
gum. Traumatized bone and torn soft tissues are fertile culture 
grounds for bacteria. Hence my objection to the "radical" 
extractionists who to-day make elaborate and useless moon shaped 
incisions into the gums to expose the outer plate of a mandible and 
then lift up this outer plate to push out the teeth laterally. The 
moon shaped flap invariably sloughs, the outer plate invariably 
dies and suffers the fate of a sequestrum, and the teeth fail to push 
out when most definitely in need of removal, for when dead they 
are anchored by scar tissue and calcification into the socket. The 
result is that the teeth break off or crumble and must in the end be 
extracted by forceps. Less total destruction is done by starting 
with the forceps. 

If the dentist bears in mind that" he is operating in the fields of 
arthritis, osteitis, osteomyelitis, he will see how next to proceed. 
Obviously infected joint linings, pus pockets and bone fragments 
whether of tooth or jaw had best be removed by curette or forceps 
at once. Bony ridges and points which will die because of inade- 
quate blood supply may be trimmed. 

A great injustice done extraction patients is an ignoring of 
proper after-treatment. Free drainage into the mouth should 
be encouraged and patients should not simply be sent home to get 
over their difficulties as best they may. The sockets remaining 
after extraction should be cleaned out daily by the dentist (pref- 
erably by mere irrigation) and the closure of the wound by soft 
tissue superficially before the bony portions are clean, be prevented. 
A good mouth wash helps much, such as a warm baking soda or 
table salt solution (teaspoonful to the glass). Magnesium sul- 
phate does well and especially to be recommended is a 1 per 
cent sodium chlorid solution with 2 per cent sodium citrate. 
To touch the pockets with a diluted tincture of iodin or one of the 
organic silver salts is not bad, though I question whether these or 
other materials have any great antiseptic action. Persistently 



850 



(EDEMA AND NEPHRITIS 



tender regions of extraction and persistently pus discharging 
sinuses have in my experience always meant fractured bone, 
osteomyelitis and infected bone fragments (often very small) left 
in the operated areas. 

The dental procedures which we have discussed will make for 
the production and the maintenance of a clean mouth. To the 
patient, however, never too sensitive to its opposite, the question 
of the restitution of his biters and grinders may seem more impor- 
tant than freedom from systemic disease, which raises the 
question of the fundamental principles that should guide us in 
the making of such restitution. 

There is at least one thing to be said in favor of the old- 
fashioned upper and lower dental plates. They may be less 
effective for biting purposes than the remains of natural teeth, 
but they are clean. The long-famous bridges attached to gold 
crowns or built upon structures pegged into half dead root re j 
mains are evidently all things of the past. To build such 
structures upon half dead teeth is to invite trouble from the 
start, while to build them upon living teeth by methods which 
insure their death is a crime. 

The clinics of Roach, Ash and Hinman and the writings of men 
like Norman B. Nesbett 1 and W. E. Cummer 2 illustrate the 
principles which must be followed and what, with genius, can be 
accomplished through partial dentures. The eternal law to keep 
in mind is that nothing must be placed in the mouth t which will 
irritate a tooth or a gum line, for such wounding must inevitably 
be followed by infection. Bridges should therefore be of the 
removable type, the teeth built on saddles well fitted and bearing 
upon the adentulous mandibular remains. The clasps which hold 
such structures in place should not grasp a tooth too low around 
the neck or impinge upon the gum edge. Where simple clasps do 
not suffice, studs may be fashioned with bearing surfaces pressing 
against teeth of the opposite side. To get a mouth clean, to make 
restitution of lost teeth through partial dentures and to accomplish 
the whole by means which will not lead to new infection in pre- 
viously sound teeth or gums — here is a problem worthy the science 
and skill of the best of men. 

1 Norman B. Nesbett: Dental Cosmos, 60, 204 (1918); Jour. Am. 
Dental Assoc., 7, 302 (1920). 

2 W. E. Cummer: Jour. Allied Dent. Societies, 11, 386 (1916). 



APPENDIX 



851 



12. Concluding Remarks 

Lest I be misunderstood, let me express again my regard for 
the splendid work our Americanjdentists have done in the way of 
preaching, teaching and bringing to pass mouth hygiene, and let me 
acknowledge the many teeth that, I think, they have saved to the 
everlasting benefit of their patients. I am not opposed to any of 
this. What we need to decide is whether there can be reached or, 
better, whether there has not now been reached the point of dimin- 
ishing returns in this matter of mere tooth preservation. My 
patients return to me from the dentist, time after time, with the 
statement that a peg tooth, a crown, a root, a piece of bridge work 
"need not come out," or that the involved tooth structures "can 
be saved." I know this in advance. What I would rather know 
is whether, at the same time, the patient can be saved. The debate 
is not between the relative merits of losing a tooth and saving it, 
but between that of the maintenance and the cure of an infection. 
I am not for extraction just because it is easy. I come to it as do 
you, as a last resort. It is not the matter of a choice between an 
evil and a good thing, but that of a choice between two evils. It 
is too often a choice between a much-desired cosmetic effect and 
illness or death; or a loss of some or all the teeth and recovery 
from systemic disease. 

Perhaps the day will come when less radical measures than 
those which, in my experience, have alone proved availing will be 
the order of the day, but progress here is going to be made, not 
through a greater attention to the mechanical aspects of dental 
surgery, but to its bacteriological and pathological sides. New 
light will come as clinical observation and laboratory experiment 
bring us a better knowledge of what are the conditions which 
render us liable to infection, whether in a tooth or elsewhere, and 
of what are the means of defense which the body uses to over- 
come such. American dentists, like their surgical colleagues, are 
to-day talking too much of mechanics and too little about surgical 
principles. There is a lot about hammers and tongs and new 
methods of nailing things together and too little, it seems to me, of 
why we live and die. 



852 



(EDEMA AND NEPHRITIS 



II 

DIAGNOSIS, PROGNOSIS AND TREATMENT IN NEPHRITIS 1 

(A Clinical Lecture) 

I am going to show you this evening some very familiar types 
of patients. There will not in any case be any debate about the 
diagnosis, and their commonness will bring to mind the routine 
service of the daily practice of each of you. I am going to com- 
ment upon these patients, and in so doing, not only indicate how 
inadequate are our present physiological and pathological inter- 
pretations of their clinical behavior, but substitute for these inter- 
pretations some less orthodox, but I think more logical ones. 

1. (Edema in the Absence of Circulation 

This young man, whom Dr. O'Connor has just presented to 
you, has kindly consented to stay a moment longer while I use him 
to demonstrate the incorrectness of our ordinary teachings regard- 
ing the nature and origin of oedema. Dr. O'Connor has just told 
us that, in consequence of an injury, this man now suffers a com- 
plete break in the circulation to the lower left leg. Below the 
knee the limb is cold and no pulse can be detected in any of its 
blood vessels. In the extremity itself the toes have become gan- 
grenous and a demarcation line is found above the ankle. Now 
observe that as compared with his right leg, his affected left is 
swollen to twice the size of the normal member, and yet, so far 
as we can make out clinically, the circulation in most of the leg 
below the knee has stopped completely. We see here, then, a 
tremendous oedema in the entire absence of any circulation. 

This finding, which you can corroborate in all types of major 
and minor injuries, at once does away with those teachings regard- 
ing the cause of oedema which look to blood pressure and changes 
in blood pressure, as primarily responsible for the production of an 
oedema. Pathology formerly taught us, for example, that because 
of an increased capillary blood pressure, liquid is forced out of the 

1 Martin H. Fischer: Lancet-Clinic, 115, 419 (1916), being the steno- 
graphic report of a lecture delivered before the St. Francis Medical Society of 
San Francisco, in the St. Francis Hospital, August 27, 1915. 



APPENDIX 



853 



capillaries into the surrounding cells, and that thereby the affected 
cells (the limb, in this case) are made to swell. 

But, as you see, we have in this patient no blood pressure 
whatsoever to call upon and yet we have a marked cedema. In 
other words, a complete absence of blood pressure seems just as 
effective in bringing about the swelling of a leg as an imagined 
increase. This means, of course, that we need to revise com- 
pletely our present conceptions of cedema and to seek the cause of 
it in other fields. That which is undebatable in this patient's 
clinical picture is that his lower leg is not getting its usual supply 
of blood. Let us, therefore, ask what happens when we thus cut 
off the circulation to an organ in a warm-blooded animal. Not 
only does there follow an accumulation of carbonic acid in the part, 
but in the absence of an adequate oxygen supply (evidenced here 
by the bluish-purple look of the skin), there are produced in the 
involved tissues various other so-called sub-oxidation acids. Lac- 
tic acid is one of them. 

To understand what these acids do, we must recall their effects 
upon protein. When gelatin or some other protein material is 
thrown into cold water, it swells, as you know. But if a little 
acid is added to the water, the swelling is enormously increased. 
And that is just what has happened in this patient's leg. Under 
normal circumstances, as in these tissues, the proteins have a 
certain normal capacity to swell. But when the amount of acid 
in the member is increased, as in this injured leg, then the proteins 
absorb a more than normal amount of water and there results 
such an cedema as we have before us. 

This leg, then, has swollen, not because an increased amount of 
water has been forced into the tissues, but because the tissues them- 
selves have suffered changes whereby their capacity to hold water 
has been increased. Because the hydration capacity of the pro- 
teins has been increased, they have been enabled to suck water 
from any available source. In the patient, this source is found in 
such remaining circulation as may be continuing in the upper, 
uninjured portions. of the leg, or in the lower margins of the intact 
circulation remaining above the point of injury. 

§ 2 

What we see here as true of a local cedema is true of general 
oedemas as well. It is a fact, little considered but entirely true, 



854 



(EDEMA AND NEPHRITIS 



that the worst cedemas observed occur in the dead if only water 
is furnished. A man killed and thrown into the water, or a man 
who commits suicide by drowning, develops an oedema in spite of 
the fact that he has no circulation left, and of course, in conse- 
quence of this, no blood pressure, either, to explain that cedema. 
What happens is that after death (really because respiration and 
circulation have ceased and so no oxygen is furnished) the normal 
oxidation chemistry of the tissues becomes changed. In other 
words, the so-called post-mortem acids are produced and act upon 
the (protein) colloids of the tissues, increasing their capacity for 
holding water. In our patient here, the source of the water is 
from the circulation bordering upon or persisting in the injured 
tissues; in the dead man it is from the lake or ocean enveloping 
him. 

With these facts in mind, let us pass to a patient in whom a 
general cedema dominates the clinical picture. 

2. The " Nephritis " of Heart Disease 

§ 1 

This second man, a painter, forty-eight years old, came into 
the hospital about seven weeks ago because of a swelling of his legs 
and some shortness of breath. For two months previously he had 
had what he calls "stomach trouble," secondary, he says, to an 
enlargement of the liver noted by the physician then caring for 
him. On questioning him, we find that the gradually ascending 
swelling of the legs was noticeable about two months before he 
entered this hospital. His account, and even a casual look at him, 
point to the ordinary oedema of cardiac origin, so you will not be 
surprised to find that his earlier history and his present state cor- 
roborate this view. Four years ago this patient had quinsy. 
Subsequently he had several attacks of rheumatism. His joints 
swelled repeatedly and became red and painful. 

At the present time he is unable to lie down. His breathing is 
rapid and shallow; we note also that it calls into play the extraor- 
dinary muscles of inspiration; his neck muscles, you see, join in 
the inspiratory movements. His radial pulse is 88; the pulse beats 
are of unequal intensity; there is a venous pulse in the neck. 
Examination of his lungs shows the upper portions to be clear, 
although the inspiratory sound is somewhat harsh. The lower 



APPENDIX 



855 



portions of the lungs are relatively dull on percussion, with distant 
breath sounds and decreased vocal fremitus. There is evidently a 
certain amount of fluid in the pleural cavities. The areas of both 
relative and absolute cardiac dullness are greatly increased. The 
apex beat is in the sixth intercostal space and a full two inches to 
the left of the nipple line. The upper cardiac dullness begins just 
below the first rib, while on the right its beginnings lie an inch 
outside the right sternal edge. The first heart sound has lost its 
booming character, and neither this nor the second is pure over 
any of the valve areas. 

We have evidently to do with a disease involving directly, or 
through dilatation, all the heart valves; and since the muscular 
element in the first sound is so largely lost we are no doubt right 
in adding to the valvular element that of insufficiency of the heart 
muscle itself. The history of the patient, the fact that he has occa- 
sional rises in temperature of an irregular type, the varying leu- 
cocytosis that accompanies these, together with the physical find- 
ings so easily elicited, lead us to the diagnosis of an infectious 
endo-myocarditis of subacute type. 

§ 2 

It is of importance to notice next his blood pressure. The 
systolic measures 125 mm. of mercury; the diastolic we are unable 
to read. Please bear in mind this value for comparison with 
some readings in other patients that I shall show you later. The 
physical evidences of cardiac dsiturbance with a blood pressure 
showing a normal systolic value, as seen in this patient, mean 
something totally different, so far as diagnosis and prognosis are 
concerned, from similar physical findings observable in patients 
with high blood pressure. 

Besides the changes in the heart and the fluid accumulations 
observable in the two pleural cavities, we note the liver dullness 
beginning an inch above its normal height in front and extending 
downward to below the costal arch. The liver is palpable a full 
hand's breadth below the arch. Propped up in bed as he is, we 
discover also that the lower tissues of his abdomen, back and but- 
tocks are swollen, and percussion shows a ring of dullness in the 
lower abdomen indicative of fluid here. For these ascitic accumu- 
lations he has been tapped several times. We note, too, that 
his legs are heavily swollen from the feet up to the hips. 



856 



(EDEMA AXD NEPHRITIS 



We have before us a man with a central pump which is no 
longer doing adequately the work it should do in pushing the blood 
around his systemic and pulmonary circuits. We need not debate 
in detail the exact character of the changes that have occurred in 
his heart. There are the obvious evidences of valvular defects, 
as betrayed by the murmurs, and of changes in the co-ordinating* 
and muscular structures of the heart itself as shown by the 
irregularity in the number and intensity of the heart beats and the 
pulse, and by the decrease in intensity of the muscular element 
on hstening to the heart sounds. Since the now classical patho- 
logical and bacteriological study of these hearts by E. C. Rosexow. 
we know them to be suffering from infection — secondary for the 
most part to such neglected foci as are represented by this patient's 
tonsils — which may involve the valves, the heart muscle, the 
pericardium, or all three. It is such a general involvement, in 
other words, a pan-carditis, that this patient shows. 

§ 3 

Let us ask now concerning the nature and the origin of the 
various clinical signs seen in this patient and so commonly observed 
in all bedridden cases of failing heart. Why, first of all, is there 
a general oedema? In consequence of the incompetent valves 
and in consequence of the decreased contractile force of the cardiac 
muscle, this patient is not pushing his blood stream through his 
circulatory tubes at the normal rate. "What must be the con- 
sequence? All the tissues of his body will suffer from two 
things — first, the carbonic acid produced normally in all living 
cells will fail to be removed from them as rapidly as it should be, 
and second, the cells will be inadequately supplied with oxygen. 
In other words, there must occur and has occurred in practically 
all the tissues of his body, what we observed in the leg only of our 
former patient. 

The history of an oedema beginning in the feet and gradually 
spreading upwards, by itself aroused our suspicion that this was a 
cardiac oedema. As we shall see later, the oedema would have 
indicated a totally different origin had it at once affected the body 
more generally, as when we observe, for example, a swelling of the 
eye-lids and a puffiness of the face going with an oedema involving 
all the tissues of the body, as in the so-called parenchymatous 



APPENDIX 



857 



nephritis. It has long been known that an oedema of the feet is 
most likely to be the first sign of a cardiac oedema because the 
distance of the feet from the heart and the maintenance of an 
upright position aid in aggravating the lack of circulation 
to the extremities induced by the weakness of the heart itself. 
By doing away with the upright position we are likely to see such 
patients improve very quickly, in other words, with no methods 
of treatment other than bed rest. 

At other times we seek aid from the administration of digitalis 
or other cardiac stimulants like strophanthus, caffein, or camphor. 
I call your attention to the use of these drugs merely to emphasize 
how absurd are the notions that an increased capillary blood pres- 
sure is responsible in the first place for the oedema. Were our 
current notions of oedema correct, these drugs that raise blood 
pressure ought to increase oedema, yet they never do. Why these 
drugs produce their good effects is understood at once if we recall 
that they act as cardiac and respiratory stimulants, thus favoring 
the circulation of blood through the cedematous tissues. This 
means, of course, a better oxygen supply to the tissues and a better 
removal of the carbonic acid and other acids formed in them, with 
consequent reduction in the capacity of the tissues to hold water 
and therefore a reduction in the cedema of the suffering tissues. 

Let us follow, for a moment, the future of the patient with 
heart disease in whom bed rest, drugs of various sorts, etc., are 
powerless to stay the progress of his disease. What are we likely 
to see? Coincident with or at times following the first swelling of 
the feet, which gradually spreads upwards, we are likely to observe 
not only a certain degree of dyspnea, but also evidences of an 
cedema of the tissues lying nearer the heart. The liver and kidney 
may become involved, both of them becoming swelled, because of a 
so-called passive congestion. We reserve a discussion of the 
changes in the kidney until later, for they furnish the stepping 
stone to the orthodox nephritides which are to constitute the 
main point of discussion for this evening. 

§ 4 

How are we to understand the mechanism by which the liver 
cedema so common in these cardiac cases is brought about? It is 
usually held that there is a backing of blood into the liver and that 



858 



(EDEMA AND NEPHRITIS 



the increased capillary blood pressure resulting therefrom forces 
blood into the liver cells. When we try to produce an oedema of 
the liver by experimental means, we find that none results from 
ligation of the portal vein. Failure of the portal blood to go 
through the liver is, therefore, not a cause of cedema in this organ. 
This fact does not surprise us. The portal blood, highly venous, 
has nothing to do with the maintenance of the liver parenchyma 
in its normal state. We have an cedema of the liver, however, 
when the hepatic vein is tied. As you know, the mixed blood 
from the portal circuit and the arterial blood entering the liver 
through the hepatic artery leaves the liver through the hepatic 
vein. The parenchyma of the liver is supplied with oxygen 
through the hepatic artery, so it is not surprising that the most 
effective way of producing an oedema of the liver is through liga- 
tion of this vessel. This deprives the liver of oxygen; and an 
abnormal accumulation here of carbonic and other acids follows. 
Ligation of the hepatic vein brings about the same general effect 
by indirect means and when heart disease leads to an cedema of 
the liver, it is to be understood similarly. Blood backed into the 
hepatic circuit dams the influx of arterial blood through the 
hepatic artery, the whole state being aided and abetted, in many 
instances, by an improper activity of the heart muscle and heart 
valves in propelling the blood forward, so that an adequately 
arterialized blood stream really never gets into and through the 
liver. 

§ 5 

As the cardiac patient fails further, he may begin to show signs 
of cedema in the upper portions of his body, as in his upper extremi- 
ties, and his face and neck. At this stage, he will probably com- 
plain of headache and appear drowsy, and coincident herewith, 
or, at times, preceding it, there may be a persistent nausea, asso- 
ciated perhaps with vomiting. While such nausea and vomiting 
are commonly, and, no doubt, with some justice, ascribed to a 
passive congestion and cedema of the stomach, I should like to 
emphasize that quite as important a factor is that of acid intoxi- 
cation of the central nervous system. Nausea and vomiting are 
common expressions of an acid intoxication with cedema of the 
medulla. I cannot press this home to you too strongly, because 
its importance is ordinarily overlooked. These signs represent 



APPENDIX 



859 



to me the earliest indication of what will shortly be a serious path- 
ological condition. The headache with drowsiness and the grad- 
ually increasing stupor are similarly to be taken as evidences of an 
acid intoxication and oedema of the brain; wherefore, these inad- 
equately appreciated signs and symptoms are also to be ranked 
among the important first danger signals informing us of the exist- 
ence of a serious state in the brain. If something is not or can- 
not be done to relieve such brain and medullary cedemas, the head- 
ache and drowsiness give way to stupor and coma, while the 
increasing medullary involvement is expressed in the heavy and 
stertorous breathing or Cheyne-Stokes breathing so frequent 
before death. 

§ 6 

If the patient does not die at this time we may find, on examina- 
tion, that the alveoli of the lungs are beginning to show evidences 
of fluid in them and that the bronchi are gradually filling; the 
patient is developing a pulmonary oedema. It is often said that 
a pulmonary oedema is the cause of death in these cardiac patients, 
but as Julius Cohnheim pointed out, many years ago, "Patients 
do not die of pulmonary oedema, they develop a pulmonary oedema 
because they are dying." The reasons for the terminal "pul- 
monary oedema" are the same as those discussed in the case of the 
fiver. Ligation of large trunks of the pulmonary artery is not 
followed by pulmonary oedema, nor is even the ligation of large 
branches of the pulmonary vein, the reasons being that the pul- 
monary circuit does not feed the parenchyma of the lung. The 
arterial blood supply to this comes through branches of the aorta, 
namely, the bronchial arteries. Because these lie so near the heart, 
the lung will continue to be supplied with arterial blood of such 
quality as may be available almost until the end, and hence it is 
nearly the last to be involved in the cedematous process. Last of 
all to be shut off from the arterialized stream 'will be the heart 
itself, for by the coronary arteries, blood will be carried through 
the heart muscle until the final stroke of the pump. 

§ 7 

Let us go back now to a consideration of the changes that occur 
in the kidney in cases of heart disease. By a mechanism similar 



860 



(EDEMA AND NEPHRITIS 



to that active in the other tissues of the body, the kidney-, too, 
develops an cedema. Through the passive congestion an inade- 
quate blood flow through the kidney is established, on account of 
which this organ also begins to suffer from an accumulation of 
carbonic acid and of other acids in it. These acids, by enabling 
the protein colloids of the kidney to hold a more than normal 
amount of water, lead to a swelling, and thus the increase in the 
size of the kidney, so common in heart disease, is accounted for. 
But at the same time that this is happening to one group of the 
colloids of the kidney a second group is being precipitated, leading 
to the appearance of granules in the kidney cells. These granules 
give the tissues a cloudy or boiled appearance, which, together 
with the swelling of the other group of colloids, -yields the combi- 
nation known as "cloudy swelling." Under the influence of the 
acids, the kidney proteins also tend to go into solution and this 
marks the origin of the albumin we find in the urine. Such albu- 
min in the urine as is not due to gross breaks in the blood vessels, 
or to an escape of the formed elements of the blood by diapedesis, 
is due to a "solution" of the kidney. Moreover, under the solvent 
action of the acid, the kidney structures tend to fall apart. Since 
the colloid material attaching the kidney cells to then base is more 
readily soluble in acid than the kidney cells themselves, the cells 
stick together and separate in groups from their tubules. This 
marks the origin of the kidney casts. Whether these shall be 
epithelial in character, granular, or hyaline, depends entirely upon 
the concentration of acid present in the kidney, the concentration 
of the various salts, and the length of time they have together 
acted upon the kidney structures. But under the influence of an 
acid the power of the kidney to give off water, in other words, to 
secrete urine, is also impaired; consequently a decrease in urinary 
output goes with the uncompensated heart lesion. 

The fact is not strange, therefore, that casts, albumin and a 
decreased water output are the almost constant accompaniments 
of every uncompensated heart lesion. Obviously the intoxication 
of the kidney with acids (and similarly acting substances) must 
increase, other things being equal, with increasing failure of the 
heart, and so we are not surprised to find that less and less 
urine is secreted, containing more and more albumin and casts, 
as the heart impairment grows. On the other hand, we are all 
familiar with the often rapid clearing of the urinary findings when 



APPENDIX 



861 



acute attacks of cardiac failure respond favorably to bed rest, 
cardiac stimulants, etc. 

The presence of an increasd amount of acid in the kidney in all 
these uncompensated heart cases is proved not only by the direct 
finding of more acid in the blood of these patients, but by an analy- 
sis of the urine. It is a familiar fact that the acidity of the urine 
in cardiac patients, whether measured by titration or in the more 
popular modern terms of hydrogen ion acidity, always shows an 
increase above the normal. 

§ 8 

Let me call your attention to an easy and rapid clinical method 
of measuring approximately the hydrogen ion acidity of the urine. 
While such a test alone does not permit us to make any absolute 
generalization regarding the state of the patient or his future, it 
nevertheless gives us some valuable points regarding treatment and 
prognosis. I would suggest that, instead of using litmus in testing 
the reaction of the urine, you use a saturated alcoholic solution 
of methyl red. This indicator is less sensitive to acids than is 
litmus. In using it, two drops of the solution are added to five 
cubic centimeters of urine. The container should be, preferably, a 
porcelain dish, or a beaker set upon a white background, and pre- 
viously cleaned in distilled water, or, if this is not accessible, first 
rinsed in the urine to be tested. We have found by clinical study 
that normal individuals at bed rest and on a full diet do not run 
a urine acid to methyl red, except perhaps in the early morning 
hours. On the other hand, cardiac cases and many others pass 
urine acid to this indicator straight through the twenty-four 
hours. 

Let me say to you that it is an acid intoxication which in the 
cardiac case ultimately kills the patient. It is, therefore, of much 
moment to discover its existence, its intensity and its persistence. 
It has been our experience that no patient recovers, be he a cardiac 
case or any other type, who secretes urine that remains persistently 
acid to methyl red. 

On the other hand, a fall "n acidity to below the turning point 
of methyl red, whether accomplished through bed rest and the 
unaided efforts of the patient in overcoming his pathological state, 
or aided, on our part, by an active administration of alkali, means 



862 



(EDEMA AND NEPHRITIS 



an improvement in our patient and a correspondingly more hope- 
ful prognosis. 

A careful following of the acidity of the urine constitutes our 
only correct guide to the amount of alkali that must be admin- 
istered. This must be given until the patient shows urine persist- 
ently alkaline to methyl red. In normal individuals at bed rest 
five grams of sodium bicarbonate, for example, will usually suffice 
to efface the acid reaction of even the morning specimens of urine. 
Cardiac cases, depending upon their severity, will require 30, 
50, or even 100 grams of sodium bicarbonate in twenty-four 
hours before this result is obtained. I have given even larger 
amounts than this by mouth, rectum or intravenously, and not 
changed the hydrogen ion acidity of the urine. In my experience, 
such cases die. When death will take place cannot, of course, be 
stated in absolute terms. It may occur in a few hours, or a few 
days; and I have never seen such patients live beyond three or 
four weeks, when it has proved thus impossible to reduce the 
acidity of the urine by appropriate means. 

§ 9 

The cedematous patient with heart disease that I have just 
showed you really represents, therefore, one suffering from a 
general intoxication. While he is primarily a sufferer from heart 
disease, he is, physiologically considered, really suffering from a 
general intoxication with carbonic, lactic and other acids. This 
acid intoxication is responsible for his general oedema including 
that of his kidneys; it is primarily responsible for all the changes 
which these organs show, and which, were we unconscious of their 
cardiac origin, we would be willing to call " nephritic." As a 
matter of fact, we might as well call them such, for this will serve 
to bring them, as it should, into close union with those similar 
urinary findings which most people are willing to concede as truly 
nephritic, but for the origin of which other factors are responsible. 
I can make this matter clear to you by showing you the next 
patient. We shall find that she, too, has been the victim of a 
general intoxication with sub-oxidation acids and like substances, 
but the mechanism by which the sub-oxidation acids were pro- 
duced in her instance was not cardiac in type — she was the victim 
of a poisoning of the exact nature of which we know as yet little or 
nothing. 



APPENDIX 



863 



3. The Nephritis of General Intoxication 

§ i 

In a patient with heart disease, an abnormal production and 
accumulation of acids and like substances in the tissues of the body 
is brought about chiefly through the inadequate supply of oxygen 
that is furnished to the tissues. Obviously, the same sort of 
intoxication would have to follow were we, with maintenance of a 
normal circulation and plenty of oxygen reaching the tissues, so 
to damage the cells themselves with a poison of some sort that they 
could not use properly the oxygen after it had reached them. We 
would then again have various abnormal sub-oxidation products 
accumulating in the affected cells, and the result would be an 
oedema of the involved tissues which, depending upon the organ 
involved and its intensity, might be of little or mueh significance; 
and depending upon the nature of the intoxication and its persist- 
ence, constitute an evanescent or death-dealing affection. The 
patient that I now show you is no longer ill, but she has just 
come through such an intoxication as I have outlined. 

§ 2 

Mrs. R. is thirty years old. She entered the hospital about 
six weeks ago, when practically at term, not because she was suffer- 
ing from any symptoms, nor because her attending physician, 
Dr. W. W. Wymore, had noted anything abnormal about her, 
but because she felt the hospital a better place than home in which 
to be delivered. Repeated urinary examinations in the hospital 
were negative. The record shows that she voided a good quantity, 
namely, from 270 to 330 cc. (9 to 11 ounces), at a time, 
several times in each twenty-four hours. Her general physical 
state continued good. She went into labor early on Sunday morn- 
ing, July 25, and toward daybreak was delivered of a normal living 
girl. The labor was not particularly hard; a little ether was used 
during the delivery of the head. Nothing abnormal was noticed 
until after delivery. Her temperature throughout her stay in the 
hospital had not risen above 98.8° F., nor her pulse above 66. 

For several hours after delivery everything continued well; 
then, waking from a period of somewhat broken sleep, she com- 
plained of severe headache. Please note this symptom, the 



864 



(EDEMA AND NEPHRITIS 



only one she had; the tremendous importance of it is not generally 
recognized by our medical men. Its significance we shall discuss 
later. 

Her urinary output diminished somewhat after delivery and a 
catheterized specimen showed it to be acid to methyl red and 
para-nitrophenol. At this time some albumin and casts were 
found. There was also apparent about the face a slight puffmess, 
and a very mild grade of oedema could be noticed in the skin 
generally. This general state continued until some twenty-four 
hours after her first labor pains, when she began to vomit. She 
seemed also more than usually drowsy. Several teaspoonfuls of 
sodium bicarbonate and two teaspoonfuls of saturated magne- 
sium sulphate solution by mouth were ordered and the patient was 
left to herself. Her headache and vomiting persisted. Several 
hours later she had a convulsion. 

§ 3 

Let us stop at this point and try to picture what had happened 
to this woman. If she had had casts and albumin in her urine 
before delivery (or, as many would say, since she had casts and 
albumin in her urine after delivery) this patient would have been 
alleged to have been an example of a so-called pregnancy nephritis 
with "uremic" symptoms. But there is something illogical in the 
view that such a patient is suffering from a retention of various 
poisonous substances which should have been eliminated through 
the kidney and hence is uremic, when she shows absolutely noth- 
ing in her urine that would indicate any disturbance in the kidney 
function. Yet this view continues uncombated throughout the 
world. But not only does the history of this patient prove con- 
clusively the absurdity of a belief which would maintain that 
such symptoms as this woman showed are secondary to a loss of 
kidney function, but animal experiments prove it. Were those 
signs and symptoms which clinically we are in the habit of designa- 
ting as uremic really secondary to a loss of kidney function, 
then we should be able to reproduce this picture experiment- 
ally through double nephrectomy in animals. But when we 
remove both kidneys from an animal, or, when surgeons by mistake 
remove an only kidney, the victims of these procedures show none 
of the signs and symptoms generally classed as uremic, although 



APPENDIX 



865 



they live many days. Even when in isolated instances they live 
two or three weeks after such accidents, they remain perfectly 
clear mentally. Neither do these patients thus deprived of their 
kidney function develop an oedema. 

Let us compare with these results those of another set of exper- 
iments. Let us give some animals one of the generally acknowl- 
edged and popular "kidney poisons" like uranium nitrate. With- 
in a few hours after the poison is administered the animals begin to 
develop a generalized oedema, amounting in the case of frogs to 
an increase in body weight of 25 to 50 per cent in one or two days. 
These animals also show a decrease in urinary output, with casts 
and albumin. They are, in other words, nephritic. But they are 
likely to be drowsy also and sometimes, on irritation, they will 
suffer a convulsion. While after double nephrectomy animals 
may live many days, these poisoned ones rarely live more than 
five or six. How are these differences to be understood? It is 
generally held that in the poisoned animals the oedema, stupor, 
etc., are secondary to a loss of kidney function, but, as you observe, 
this interpretation cannot be correct. 

The animals poisoned with uranium nitrate present the same 
picture that this woman did when, several weeks ago, she was 
suffering from an intoxication incident to her pregnancy. In 
both instances the whole organism is the subject of a general 
intoxication. As it strikes the kidneys, the intoxication produces 
an oedema of these organs, with the appearance of albumin and 
casts; as it affects the subcutaneous tissues, an oedema results 
here; and as it affects the brain and the medulla, these organs 
swell, thus giving rise to the headache, the nausea, the vomiting, 
and ultimately the stupor, coma, convulsions and death, which so 
frequently close the scene. They are the victims not of an uremia, 
but of an acute toxic oedema of the central nervous system, and 
this is not secondary to an imagined loss of kidney function — in 
the case of this patient, as you will remember, there were at first 
no kidney signs whatsoever — but due to the direct action of the 
toxic agent upon the central nervous system itself. The brain 
effect is not secondary to the kidney disturbance, but both are 
due to the same cause. 

I cannot emphasize too strongly the importance of getting 
this relationship clearly in your minds. How often are we stopped 
by one of our colleagues who informs us that some patient, to his 



866 



(EDEMA AND NEPHRITIS 



great surprise, has just died in coma and convulsions, when, as in 
this patient, the urinary findings were trifling in nature, or entirely 
normal. So long as we make the head symptoms secondary to the 
kidney findings, this mistaken feeling of security will go on. But 
when once we recognize that the head symptoms and the kidney 
findings represent pathological processes of the same type — essen- 
tially oedemas — and that the one is not consequent upon the other, 
but that both are due to the same toxic agent acting simultaneously 
upon different organs, a better understanding of our clinical prob- 
lem will result. 

A poison injected into an animal or produced in a human being, 
need not, of course, involve all organs equally or at the same rate, 
and so it happens that in these pregnancy intoxications we may 
find the signs from the kidney predominating at one time, at 
another those from the head. More rarely the liver is chiefly 
involved, and then we speak of an " acute yellow atrophy," a 
" chloroform," or " ether liver," or something of that sort, indicat- 
ing that the liver has been the chief sufferer in the general intox- 
ication. I have seen pregnancy patients with suppression of 
urine lasting days, but the brain completely clear, and I have also 
seen convulsive seizures in women who showed no abnormal 
urinary findings whatsoever. These things mean that in the 
former instance, the kidneys were more acutely poisoned than the 
head, while in the latter it was the brain that suffered the more 
severely. 

This is the reason for the importance of headache or nausea, 
drowsiness or vomiting in pregnant women. These cause me more 
anxiety than complete suppressions of urine, for they represent, 
in essence, symptoms of a dangerous degree of brain swelling, and 
therefore betray a condition which portends greater immediate 
danger, and which is combated with greater difficulty than a 
complete suppression of the kidney function' 

§ 4 

The patient before us had, at the end of her first eighteen hours 
after delivery, little evidence of a kidney or general tissue involve- 
ment. Her first symptoms and signs pointed to an oedema of 
the brain, and it was toward this, more specifically, that first 
attention was directed. Beginning with headache, she developed 



APPENDIX 



867 



nausea and vomiting, following which there came stupor and a 
convulsion. 

Please remember that these signs began after delivery. I have 
heard more than one of my critics say that the good results which 
follow such treatment as was given this patient are but accidental, 
and that even without such treatment these patients, after delivery, 
"take their natural course." I regret deeply that this "natural 
course" is not usually along the road toward life, but more com- 
monly toward the great beyond. It is a fact little remembered 
that one-third, and according to some authors, one-half of all the 
convulsive seizures incident to pregnancy do not develop until 
after delivery. That is what happened in this patient. 
The reasons are to my mind perfectly clear. Before delivery 
these patients usually show a high degree of acid intoxication, 
although it may not have reached the point of producing an 
cedema of the kidney, of the head, or of some other organ. But 
to the initially high acid content, add the element of acid produc- 
tion incident to the muscular efforts of labor, or that of the acid 
intoxication consequent upon narcosis (whether by chloroform, 
ether, morphin or scopolamin) , and the sum of the two is sufficient 
to push many a woman who has just managed to drag herself 
through her pregnancy, over the line. So in this patient head 
symptoms first appeared after the fatigue of delivery, as did the 
albumin and casts. 

§5 

The administration of sodium bicarbonate and of magnesium 
sulphate in several small doses represented a first attempt to meet 
the cedema of her brain, that of the kidneys as expressed in her 
urine, and that of her tissues generally, as observed in her slight 
general cedema. This mild scheme of therapy permitted her to 
hold her own with decrease in the intensity of her various symp- 
toms and signs for about three days, when her headache again 
became very severe, her nausea and vomiting reappeared, her 
drowsiness rapidly increased, and another convulsion took place. 
The patient then went into a coma from which she could not be 
roused. While in this state, a series of major and minor convul- 
sions occurred. 

Very clearly we had not been sufficiently aggressive in our 



868 



(EDEMA AND NEPHRITIS 



dehydration therapy. Urine obtained by catheterization at this 
time proved acid to methyl red and para-nitrophenol, and was 
filled with albumin and casts. In other words, in spite of the 
steady administration of alkali, we had given not nearly enough. 

§ 9 

As you know, two elements are of much importance in deter- 
mining the amount of water that a simple protein or a tissue holds. 
When fibrin, for example, is put into water it swells somewhat, 
but if put into acid it swells very much more. Neutralization of 
the acid with an alkali reduces the swelling. But even without 
neutralization of the acid we can decrease the swelling by adding 
various salts to the acid. The amount of reduction thus produced 
is determined by the concentration of the salts, the dehydration 
increasing with every increase in the concentration of the added 
salt. 

In order to dehydrate our patient more effectively, more partic- 
ularly in order to dehydrate her brain, we decided upon the admin- 
istration of alkali and sodium chlorid intravenously. A mixture 
that may be safely used and which contains both alkali and a 
readily diffusible salt in sufficient concentration to bring about a 
dehydration of cedematous tissues, has the following composition: 

Sodium carbonate " dried " 8.4 grams. 

Sodium chlorid 28 grams. 

Distilled water, enough to make 2000 cc . 

We gave 1800 cc. of this mixture through a vein in the bend of 
the elbow, taking some fifty minutes to make the injection. 

Our patient had no more convulsions after this first injection. 
It became possible to rouse her slightly and a perceptible increase 
in her urinary output took place, with a fall in acidity to below 
methyl red. The patient continued in this state until the evening, 
when, because she had not yet cleared mentally, we decided that 
more dehydration of the brain was necessary. What to do in our 
continued efforts in this direction had next to be considered. We 
might have repeated the alkali-salt mixture first used, but for 
reasons that I shall try to make clear, we decided that an intra- 
venous injection of magnesium sulphate was better. Generally 
speaking, the greatest dehydration of the body colloids that can 



APPENDIX 



869 



be produced is obtained when they are kept in a neutral medium 
of high salt content, and it is this state that we should try to induce. 
An index to the attainment of a neutral state in the body, as when 
alkalies are being administered, is furnished by an examination of 
such different secretions from the body as urine, saliva, and sweat. 
We should attempt to get and maintain these persistently neutral 
to litmus. Even when this point has been reached and held for a 
short time it is, of course, still possible for local organs to be har- 
boring more acid than normal; but if the secretions from the body 
are kept persistently neutral, or, for a time, even slightly alkaline, 
it is reasonable to suppose that all the tissues of the body must 
ultimately also attain this reaction. 

By injecting alkali intravenously, we had succeeded in causing 
the originally high acidity of the urine to fall somewhat; and by 
administration of alkaline waters fortified with sodium bicarbonate 
and magnesium oxid, we succeeded in holding our patient neutral. 
We were, therefore, evidently giving her the best possible chances, 
from this point of view, of recovering from her brain oedema. But 
as she did not clear as rapidly as we could wish, in other words, 
did not wake up thoroughly, we knew that more brain dehydra- 
tion was imperative and so looked about for additional help. 

§ 7 

The dehydration of a protein outside of the body by salts 
depends not only, as I have already indicated, upon the concen- 
tration of salt used, but also upon the kind of salt. Certain salts 
are far more powerful in this regard than others. Calcium, for in- 
stance, is a more powerful dehydrant than magnesium, and mag- 
nesium is more powerful than sodium. On the other hand, a 
sulphate is more powerful than an acetate, iodid or bromid, and 
these in turn act more strongly than a chlorid. 

In the first intravenous injection, sodium chlorid in a more 
than " physiological" concentration was used to accomplish the 
dehydration of the brain. Not finding it as effective as we could 
have wished and satisfied on the whole with the degree of alkali- 
nization that had been accomplished, we turned to the use of a salt 
which would act more strongly than the sodium chlorid. Since 
experimental study has shown magnesium sulphate to be, roughly 
speaking, about sixty times as powerful a dehydrant, molecule 



870 



(EDEMA AND NEPHRITIS 



for molecule, as sodium chlorid, we decided to .use this material 
intravenously. 

This salt may be used safely in the form of a sterile 2 per 
cent, or 2\ per cent solution, and in amounts up to 8 grams 
of the salt. Ordinarily 200 cc. of such solutions constitute 
the ideal amount for a first dose. If this alone does not yield 
the desired effects, the dose may be repeated. This is better 
than giving a single large dose once. The injection must, more- 
over, be made slowly. After injection into the blood, 'the salt 
diffuses into the tissues and dehydrates them. As water is freed 
from the tissues, it pours into the blood stream, which is thereby 
increased in volume. This brings about an increase in blood 
pressure, which is maintained until the liberated water is lost from 
the body through one of the secretions, as the urine or sweat. In 
order not to overwhelm the circulation with too large an influx of 
water at one time, slow injection, in other words, careful dehydra- 
tion of the body tissues, must be insisted upon. 

It was after an injection of 250 cc. of a 2 per cent mag- 
nesium sulphate solution that our patient woke up completely. 
When she became conscious we questioned her regarding herself, 
and, with due care not to suggest the answers we might like to 
hear, we asked about her headache, her nausea, and her vomiting. 
For a number of hours after the injection of the magnesium sul- 
phate these S3 r mptoms were absent, and we contented ourselves by 
trying to hold what we had won through administration of alkali 
and magnesium sulphate by mouth. But some twelve hours after 
the magnesium sulphate injection, she again became drowsy, and 
complained of headache and nausea. This was an indication to 
us that her brain swelling was again increasing, so a second dose of 
magnesium sulphate was given as before. Full consciousness 
returned, and her nausea and vomiting disappeared. As she 
awoke, however, she showed a mental disturbance, which the 
psychiatrists would have diagnosed as a mild mania. She talked 
excitedly in answer to our questions, did not know where she was, 
did not recognize the members of her family, and was otherwise 
confused in mind. This mental disturbance continued about 
five days. Since we regarded it as but another expression of her 
central cedema, we kept on during this time with sufficient alkali 
by mouth to keep her urine persistently neutral, and with enough 
saturated solution of magnesium sulphate in small doses to yield 



APPENDIX 



871 



two or three easy evacuations of the bowels in each twenty-four 
hours. The primary purpose in giving magnesium sulphate was 
not the catharsis, but absorption of the salt and the maintenance 
of a steady tissue dehydration. During the five days that such 
therapy was continued, the general oedema disappeared from the 
body and the albumin and casts steadily diminished. By the sec- 
ond day the urine was almost clear and by the third it was en- 
tirely so. 

§ 8 

I cannot help commenting upon the mental state of this 
patient. It seems so obvious that the purely puerperal manias 
are only toxic oedemas of the brain, that I cannot help won- 
dering whether much could not be done for many of the manias 
due to other causes, which fill our insane asylums, if they, too, were 
treated on the assumption that they are suffering from cerebral 
cedemas. Autopsy findings in many instances show nothing more. 
In our eclampsias, a general toxic cause of unknown origin is 
responsible for the mental disturbance, and similar intoxication 
seems to underlie at least some of our orthodox psychiatric cases. 
Or such brain cedemas with their resultant abnormal mental 
states, as seen in our insane asylums, might be due to direct infec- 
tions of the brain, or to disturbances in circulation as produced 
by arteriosclerosis, the whole set of changes being the same in result 
but different in their origins, as when similar changes affect the 
kidney or some other organ. While the possible fruits of treat- 
ment and the prognosis would depend upon the nature and the 
persistance of the causes leading to the cerebral cedemas, much 
could to my mind be done to relieve at least some of these patients 
if they were made the subjects of an adequate dehydration therapy. 
My own opportunities to test out these ideas have been rather 
limited, and probably must continue to be ; but it is a study which 
some of our psychiatric colleagues could undertake without harm 
to their patients and possibly with much good. 

§ 9 . 

Every effort was made throughout this patient's illness to feed 
her, no restriction being placed upon the character of her food. 
Milk and eggnogs (without whisky) were given every three 



872 



(EDEMA AND NEPHRITIS 



hours in as large quantities as she could be made to swallow, while 
orange juice, grape fruit, mushes and gruels, all well sugared, were 
pushed to the utmost. It is most important that all these patients 
have plenty of food, and that special care be taken to administer 
enough carbohydrate. There is no objection to allowing proteins; 
I give them as soon as the patient will swallow them and of a kind 
that appeals to the appetite of the individual. It is absurd to 
think that the proteins of milk, of eggs, or of white chicken are 
any better than the proteins of beef, of mutton, or lamb (since 
before absorption they are all broken into the same forty amino- 
acids), and so I make every effort to take these patients off their 
nearly always inadequate "light" and "slop" diets so popular in 
our hospitals, and to give them good mixed rations of bread, 
toast, potatoes, rice, vegetables, steaks, chops and fish. On such 
a regimen this patient cleared completely in less than a week, and 
after about ten days spent in convalescence, she left the hospital 
in as good a general condition as most women show after a normal 
pregnancy. 

§ 10 ,. 

To the use of alkali, of hypertonic sodium chlorid and of mag- 
nesium sulphate, it is frequently well or imperative to add glucose 
(dextrose) . Because of inadequate feeding, because of the vomit- 
ing of such food as has been taken, and for certain other reasons, 
pregnant women frequently suffer from carbohydrate starvation, 
so that they become the victims of a deranged body chemistry 
quite similar to that of diabetics. In other words, their tissues 
produce large quantities of the acetone bodies (acetone, diacetic 
acid, beta-hydroxybutyric acid). If something is not done to 
stop the formation of these substances or to neutralize their toxic 
effects (as by the administration of alkali), the patients add the 
acid intoxication from these sources to any other acid intoxication 
from which they may be suffering. In all pregnant women, 
whether nephritic or not, it is therefore important to discover if 
evidences of such a carbohydrate starvation are at hand. 

Without resorting to the more refined methods for determining 
qualitatively and quantitatively the "acidosis" compounds present 
in the urine, it is certainly an easy matter to do the ordinary tests 
for diacetic acid, or acetone. It is a safe error to regard every pa- 
tient showing a persistent ferric chlorid reaction in the urine, for 



APPENDIX 



873 



example, as suffering from carbohydrate starvation and to make 
special efforts in all such patients to supply the deficit in carbo- 
hydrate intake. When such deficit is noted in a pregnant woman 
who is in coma or convulsions, or is showing an alarming lack in 
urinary output, the twin necessities of feeding carbohydrate and 
of producing a dehydration of some one or all the tissues of the 
patient may be well satisfied by giving concentrated glucose (dex- 
trose) solution intravenously. Sterile 45 per cent solutions 
in amounts from 100 to 200 cc. at a dose do very well. These 
injections, too, must be given slowly, and it is better, for the 
reasons already discussed, to give several smaller injections than 
a single large one. Since the body uses up several hundred grams 
of carbohydrate (400 to 500) in each twenty-four hours, an over- 
dose of glucose can hardly be given. Such intravenous injections 
serve the purpose of furnishing food, while they produce at the 
same time the necessary dehydration. 1 

§ 11 

A word must be said regarding the administration of water to 
these patients. When we are actively engaged in trying to dehy- 
drate the body tissues by any scheme whatsoever, it is obviously 
wrong to administer water by mouth or otherwise, for dehydra- 
tion depends upon the establishment in the tissues of an increased 
concentration of alkali or salt or sugar. No water should, there- 
fore, be given for two or three hours following our attempts at 
dehydration. But once the dehydration has been accomplished 
and physiological conditions in the involved organs have been at 
least partially re-established, then, if we desire more urine than is 
being put out, or more of some other secretion from the body, we 
can accomplish this only by furnishing the secreting glands free 

X R. T. Woodyatt (Jour. Amer. Med. Assoc., 65, 2067 (1915)) has devised 
an injection apparatus which will give accurately and at any concentration, 
any amount of glucose that we may wish to give a patient, and for any length 
of time. No further injury need be done the patient than is incident to the 
insertion of a hypodermic needle into a vein. Aside from its immediately 
practical value, Woodyatt's work is of fundamental biochemical and clinical 
interest as it establishes accurately for the first time, the toleration limits 
of various sugars. For dextrose this limit is 0.85 gram per kilo per hour, 
above which come into play its dehydration effects upon the tissues with 
the resulting rise in the various secretions, more particularly the urinary 
secretion (diuresis). 



874 



(EDEMA AND NEPHRITIS 



water. Obviously, therefore, judgment is required to know when 
to withhold water and when to press it, the matter being governed 
by the relative importance of the effects we wish to obtain — in 
other words, whether in the given clinical case the dehydra- 
tion of a certain organ is the vital consideration, or whether the 
furnishing of free water to an active gland is the end sought. 



§ 12 

What is the prognosis so far as the kidney is concerned in one 
of these pregnancy nephritides? If these patients do not die in 
their eclampsias and we succeed in clearing the urine of patho- 
logical findings, the prognosis is entirely good. These patients 
do not go on to a chronic nephritis, nor do they retain any increased 
tendency toward it. They are not more than commonly liable to 
renewed albuminuria, to uremia and other things of this type, as 
is so generally taught. Once over their pregnancy and cleared 
of the pathological findings incident thereto, they are as good as 
before. The termination of pregnancy means a termination of their 
intoxication, and if we have succeeded in protecting them from the 
consequences of this they have recovered permanently. 

We should always be suspicious of the nephritis that con- 
tinues after delivery and in which a proper attempt has been made 
to clear the urine with alkali, salt and adequate feeding. The 
nephritis is then almost certainly not purely of pregnancy origin 
but has other causes also. The more usual possibilities are that 
the kidney is the seat of an infection, or that it is the victim of 
vascular (arteriosclerotic) change. Just because a woman hap- 
pens to be pregnant, a nephritis which she may show must not at 
once be attributed to the pregnancy. Pregnant women may be- 
come nephritic from any of the causes that may strike you or me. 
An infection of the kidney, or the consequences of arterial disease, 
may come to light for the first time in a pregnant woman quite as 
easily as in anyone else. This possibility of causes other than 
the pregnancy for these kidney changes needs, therefore, always 
to be borne in mind in determining the meaning and prognostic 
importance of the casts, albumin, etc., found in the urine of a 
patient, before, during, or after pregnancy. 



APPENDIX 



875 



§ 13 

When once it is recognized that a pregnancy intoxication 
represents a general one affecting all the body cells, but which may 
make certain organs, like the kidney or brain, the chief sufferers 
and so have these dominate the general picture, the relation 
between this type of patient and that of all other patients suffering 
from a general intoxication is seen to be very close. The common- 
est clinical types of such other general intoxications are those 
incident to the anesthesias with chloroform, ether or nitrous oxid, 
and those secondary to heavy doses of alcohol. But this general 
type of intoxication is also characteristic of the action of the vari- 
ous metals, as lead, uranium, tin, zinc, mercury and arsenic (or 
its various derivatives like salvarsan, neo-salvarsan, etc.). The 
clinical picture of poisoning with any of these is much the same, 
and they all simulate clinically a pregnancy intoxication. There 
is a tendency toward a general oedema, toward stupor, coma and 
convulsions; or, when the kidney is involved, casts and albumin 
with a decrease in urinary output. But just as in the patient I 
have been showing you, none of these things is secondary to some 
other — the head symptoms are not secondary to the kidney signs, 
for instance — but all are equally due to the primary intoxication 
which tends to attack all the cells of the body at the same time. 

§ 14 

• It is clear that when a nephritis develops in consequence of 
some soluble poison passing through the kidney, as occurs in any 
of the general intoxications, the poison must tend to involve the 
whole kidney at once and more or less equally. The same thing 
is true, of course, if in consequence of a circulatory disturbance 
the whole kidney is at once made the subject of a state of lack of 
oxygen. In all such cases, therefore, the whole kidney becomes 
swollen and grayish, the secretion of urine drops to little or noth- 
ing and such urine as comes is heavily charged with albumin and 
casts. Conversely, a decrease in the urinary output, much albu- 
min and many casts, are generally to be regarded as signs indicat- 
ing that the whole kidney is involved. These things should be 
borne in mind, for they help us to interpret properly our clinical 
pictures. 

You will observe that the signs and symptoms I have detailed 



876 



(EDEMA AND NEPHRITIS 



constitute the group generally held to be characteristic of (gener- 
alized) parenchymatous nephritis. Our older clinical teachers 
used to tell us that this type of nephritis was commonly associated 
with a generalized oedema, the first evidence of which was likely 
to show itself in a puffiness about the eyes. After what has been 
said, this generalized cedema is evidently not be to regarded either 
as characteristic of, or secondary to the parenchymatous nephritis. 
It only shows that the patient as a whole is the subject of a general 
intoxication. Since the toxic agent may attack and produce 
an cedema anywhere in the body, it does not surprise us that the 
eyelids should be particularly liable to present the first evidences 
of disturbance, for these tissues have a particularly great capacity 
for absorbing water. 

4. Spotty Parenchymatous Nephritis Due to Infection of the 
Kidney (Infectious Nephritis) 

§1 

The kidney may evidently become the victim of a pathological 
process which does not destroy the whole kidney uniformly and at 
once, but affects only pieces thereof. Thus, micro-organisms may 
be sown into the kidney, and according to their lodgment may 
give rise to areas of local intoxication and death. But between 
the spots thus affected (which show the same series of changes that 
we observed before in the whole kidney, in other words, those of a 
spotty parenchymatous nephritis), we have entirely normal kidney 
substance. Let me call your attention to the fact that when we 
reduce the kidney substance in animals to one-fourth of the total 
amount, or even less, by removing first one-half or more of one 
kidney and later the whole of the opposite kidney, these animals 
show no decrease in urinary output, no casts or albumin, nor 
anything else to indicate that they are not entirely normal. Func- 
tional tests, be these water tests, or dye tests, or what not, all yield 
entirely normal findings in such animals. In other words, so far 
as kidney function is concerned we do not seem to suffer from any 
lack of it as long as one-fourth of the kidney substance is preserved 
intact. Or, to turn the matter about, our present tests yield no 
evidences of impaired kidney efficiency until more than three- 



APPENDIX 



877 



fourths of the normal total of kidney tissue or of its functional 
capacity is destroyed. 

These facts are of importance, you observe, because they 
explain why patients with a spotty parenchymatous nephritis, 
whatever its origin, do not show a decreased urinary output or a 
decreased elimination of any such substances as come out normally 
in the urine, or a decreased elimination of such as are introduced 
from without to indicate degree of function even though goodly 
portions of their kidney are in a state of active destruction. 

I have no patient here to illustrate this infectious type of 
spotty parenchymatous nephritis, but to fill in the gap let me 
read the history of one such case. 

§ 2 

Miss H., aged forty-one years, and a teacher by occupation, 
gives a family history which does not interest us. For four years 
she has not t>een able to do her work because constantly below par 
physically. She has occasionally been the victim of " stomach 
trouble," characterized by a sensation of pain in one spot in the 
stomach shortly after eating. There have, however, been no 
recent attacks of this type. During one such attack she vomited 
red blood and at another time she observed that her stools were 
very black. About two years ago, albumin and casts were found 
in the urine and have been present constantly since. 

Physical examination of the patient reveals rather prominent 
eyeballs with a lagging of the upper lids, but no tremor and no 
increased heart rate. The thyroid gland is perceptibly enlarged; 
physical examination of her heart and lungs is negative. Some 
tenderness on pressure can be elicited in the midline below the tip 
of the xyphoid process. There is no tenderness in the abdomen 
elsewhere. The legs' are negative. The sockets of several teeth 
are infected and the gums about them, red and swollen. The 
tonsils are large and red, showing crypts filled 'with caseous 
material. The lymphatic glands of the neck on both sides of the 
sterno-cleido-mastoid muscle are readily palpable. The systolic 
blood pressure is 125 mm. of mercury, the diastolic, 88. In each 
twenty-four hours, 1500 to 3000 cc. of urine are voided, depending 
upon the amount of fluid administered. When in bed, the patient 
shows only occasional specimens of urine acid to methyl red. 



878 



(EDEMA AXD NEPHRITIS 



Six to eight grams of albumin are found in the liter. Microscopic 
examination of the urine shows relatively few casts, but large num- 
bers of white blood cells. 

On the basis of these findings, a diagnosis was made of chronic 
tonsillitis and chronic alveolitis with metastatic infections of the 
thyroid (chronic thyroiditis), the stomach (chronic gastric ulcer) 
and the kidney (infectious nephritis). 

The patient consented to the removal of her tonsils and those 
teeth most badly infected. With only this, and a scheme of out- 
of-doors' living, plenty of mixed food, and the administration of 
enough sodium bicarbonate and magnesium oxid daily to keep 
her urine constantly neutral to litnius, she has improved steadily 
during the past two months so that at present she feels in better 
general health than for years, while a mere trace of albumin 
remains, and casts can be found in her urine only after long search. 

§ 3 

This patient illustrates a common type, and one frequently 
diagnosed as " chronic Bright's disease" or something of the sort, 
with a gloomy prognosis attached. Experience seems to indicate 
that such despair is hardly justified, especially if the patient will 
agree, as did this one, to a thorough cleaning up of those neglected 
foci of infection which keep seeding the blood stream with bac- 
teria, and so producing new infections as soon as older ones have 
been overcome. 

The diagnosis and proper classification of this type of infected 
kidney depend upon the recognition of points of infection from 
which the kidney condition may have arisen, upon the absence of 
changes in blood pressure, the absence of cardiac hypertrophy and 
the discovery in the urine of more than the occasional leu- 
cocytes that may be found in any acute toxic nephritis. The fact 
that the urinary secretion per twenty-four hours is normal and 
may readily be increased through the administration of water is 
evidence that the whole kidney is not involved, or conversely 
expressed, the kidney involvement is spotty in type. The urine 
only occasionally running acid to methyl red, and the albuminuria 
continuing, even after the mixed urine is kept steadily neutral to 
litmus, are further evidence in this direction. Spots in the kidney 
may, in other words, be dying of a local intoxication with acid 



APPENDIX 



879 



(and like substances) without this acid being sufficient in amount 
to make the whole urine (in other words, that coming from both 
the diseased and the well portions of the kidney) acid to methyl 
red. 

§4 

As in this patient whose history I read to you, the prognosis is 
remarkably good in all of these patients if we succeed in freeing 
them from their original foci of infection, and then by hygienic 
methods aid them to overcome the kidney state. Patience is, 
however, necessary to attain these ends. The kidney findings 
have not, in my experience, proved apt to clear quickly. At the 
best, weeks or months may be required, while others only gradually 
reduce their, albumin output from several grams per liter to a 
trace, discoverable occasionally, in the course of years. 

While it is common, even without treatment, to see these pa- 
tients with infected kidneys improve, they may also, of course, grow 
worse. There is always the possibility that the infection will 
become more general in the kidney, either because an original 
infection spreads through the kidney, soon to involve the whole 
organ, or because new infections are repeatedly sown into it. 
The originally spotty parenchymatous nephritis has then become 
a generalized parenchymatous one, and as this happens, a drop 
in urinary output to the point of complete suppression may follow, 
while the relative and absolute amounts of albumin, casts, etc., 
increase steadily in such urine as may be secreted. Sometimes 
such patients also come to show a generalized cedema, but for 
reasons that I have already tried to make clear, this is not to be 
interpreted as secondary to the kidney change ; it is a toxic cedema 
due to the absorption of poison from the affected areas in the 
kidney or from infected foci elsewhere in the body, and to the 
general toxic effects exerted by these substances upon all the 
tissues. 



880 



(EDEMA AND NEPHRITIS 



5. Spotty Parenchymatous Nephritis Due to Vascular Disease 
(Chronic Interstitial Nephritis) 

A. Ambulatory Type 

§1 

The next patient that I show you is Mrs. E., aged forty-nine 
years. She came to us some seven weeks ago, with a diagnosis of 
chronic interstitial nephritis and high blood pressure. Her chief 
complaint was headache. She had also had attacks of pain over 
the heart and radiating into the left arm. She informed us that 
for several years her blood pressure had stood as high as 280 mm. 
of mercury and that it had never fallen below 210 mm. One of 
the several physicians who have cared for her once found some 
albumin and a few casts in the urine several years ago, but repeated 
examinations since by other men have always proved negative in 
this regard. 

Physical examination on her first visit to the office showed a 
systolic blood pressure of 275 and a diastolic of 140 mm. of mer- 
cury. The lungs and abdomen proved negative. The areas 
of absolute and relative cardiac dullness were increased in all 
directions but no murmurs were noted. The arteries were pal- 
pably thickened wherever they could be felt. Scattered over 
the body, particularly noticeable in the legs, were numerous 
veins with thickened walls. When I first saw the patient she 
possessed a row of heavily infected loose teeth in the lower jaw 
and, in the upper jaw, several heavily infected and loose teeth 
carrying bridges. To-night she shows full upper and lower plates 
of false teeth. 

§ 2 

In place of the primary diagnosis of chronic interstitial ne- 
phritis, I believe it more correct, for reasons that I shall explain 
immediately, to make the primary diagnosis in this woman read, 
generalized vascular disease (arteriosclerosis and varicose veins). 
Secondary to this, there has developed cardiac hypertrophy; and 
also secondary to the vascular disease, certain symptoms and 
signs referable to the head and to the heart and, on a previous 
occasion, to the kidney. 



APPENDIX 



881 



Why, first of all, do I reject the primary diagnosis of chronic 
interstitial nephritis? She may have a chronic interstitial ne- 
phritis, but it is certainly not an important element in her present 
condition. To regard it in this patient, or in any similar patient, 
as of primary importance is not only to be wrong in diagnosis, but 
what is more important, to go wrong in the matter of treatment. 
Repeated urinary examinations in this patient, which I have made 
personally, have remained negative. This seems also to have been 
the experience of various other physicians who have cared for her. 
There exists no objective reason, therefore, for our thinking that 
the kidney element is an important one in this case, and it con- 
fuses our entire notion of what is the primary trouble, if in just 
such instances we go on maintaining what is perfectly untrue, 
namely, that the cardiac hypertrophy and high blood pressure 
are secondary to a kidney disease of which we find no evidence, 
and that the headaches of which this patient complained so 
bitterly are evidences of a " uremia." Not only do animals, or 
patients, deprived of their kidney function by sudden or more 
gradual means, never show any increase in blood pressure, nor a 
cardiac hypertrophy, nor head symptoms at all identical with 
those which clinically we are constantly given to designating as 
uremic, but the picture, which this woman and others like her 
show, can be more easily and more logically interpreted in a totally 
different fashion. 

The primary thing in this woman is the affection of her blood 
vessels. In consequence of their thickening, loss in elasticity 
and " spasm," more work is required of the heart in the unit of 
time, in other words, greater power to force the blood through the 
diseased blood vessels. The musculature of the heart meets an 
increased demand for work in the same way that the musculature 
of the blacksmith's arm meets it, namely, by hypertrophy, and 
hence the larger heart in this woman. But with narrowed blood 
channels, the minimum of blood necessary to meet the physio- 
logical demands of any organ can evidently be maintained only as 
the blood is pumped into the organ at a higher pressure. The 
cardiac hypertrophy and the high blood pressure are not in them- 
selves, therefore, to be regarded as something evil for these patients. 
They alone make it possible for the various organs suspended 
from the circulatory tree to continue their normal functions. As 
the next case will prove to you, it is not high blood pressure, but 



882 (EDEMA AND NEPHRITIS 

rather the inability to get it that kills so many of these patients 
alleged to be perishing of chronic interstitial nephritis. 

§ 3 

What are so generally interpreted as the consequences of 
chronic interstitial nephritis are really the consequences of the 
vascular disease affecting different organs. As you know, vas- 
cular disease does not affect all the blood vessels of the organism 
either uniformly or with equal intensity. The pathological 
changes consequent upon vascular disease may in one patient 
involve predominantly one organ, while in another a totally dif- 
ferent one is chosen; and depending upon which organ, or organs, 
are chiefly affected, the symptoms and signs in one patient will 
be totally different from those in another. 

In the patient before you, the vascular disease has affected 
chiefly the circulation to the head and to the heart itself. In 
consequence of a vascular disease affecting the coronaries and their 
branches, the heart muscle is periodically deprived of an adequate 
oxygen supply, which is manifested in the periodic pain seizures 
(angina pectoris) felt by this patient not only in the heart itself, 
but in the arm. 1 The same vascular disease, as it has affected 
the circulation to the brain, is responsible for similar periods of 
lack of blood here, and hence the periodic brain cedemas that are 
expressed in the periodic headaches so much complained of. 

Had the vascular disease in this patient happened to strike the 
kidneys, piece after piece of the parenchyma would have become 
cedematous and died. As these pieces became affected, casts 
and albumin would have appeared in the urine, the number and 
amount of which would depend upon the amount of the kidney 
thus attacked. But as long as one-fourth of the total amount of 
kidney substance remained unaffected, the urinary output would 
have been normal, all functional tests would have yielded normal 
figures, and, so far as the kidneys were concerned, the patient 

1 1 am accepting here the commonly given explanation for the pain 
seizures of angina pectoris. Arthur Dunn emphasizes that physical examina- 
tion of the heart during an angina attack reveals nothing analogous to the 
disturbances observed physiologically when the coronary circulation is 
interrupted. His criticisms may compel a revision of our present views. 
Dunn holds a periodic stretching of the heart ring or the first portion of the 
aorta as more probably the etiological factor. 



APPENDIX 



883 



would never have grown conscious of any trouble. Very com- 
monly the kidneys are thus affected in vascular disease and, in 
consequence of the gradually progressing destruction of piece 
after piece in the kidney, we get the picture which at autopsy we 
call chronic interstitial nephritis (small red kidney). But in the 
patient before you little or none of this particular type of change 
has occurred. 

Recall, for a moment, the high blood pressure which this 
patient has shown and still shows, and then consider how stupid 
are our notions when such pressure is attributed to "kidney 
disease." I have a number of patients in my care now in whom 
the blood pressure is constantly running above 200 mm. of mer- 
cury. Two that I remember at this moment have for years been 
carrying a blood pressure of 280 and yet they have never had an 
albuminuria, at any time. I call your attention to these facts to 
emphasize how we have gotten cause and effect turned about. 
It is not the kidney disease that leads to the high blood pressure, 
cardiac hypertrophy, etc., but it is the vascular disease which, when 
it happens to affect" the kidney, gives rise to the albumin and casts. 

The defective circulation to all or parts of various organs 
affected by vascular disease may be attributed to (a) largely 
irremediable scarrings of the blood vessels and (6) more tempor- 
arily acting factors which decrease their caliber and elasticity. 
The degenerated and calcified patches in the blood vessels come 
under the first of these headings ; while under the second may be 
listed any agency or agencies capable of producing vaso-constriction. 
For this reason the taking of food (especially protein), muscular 
work, low degrees of acid intoxication, slight exposure to lowered 
temperature, etc., all tend to raise the blood pressure of anyone, 
or to raise further the abnormally high pressure characteristic 
of the victim, of vascular disease. But most important for the 
arteriosclerotic is the fact that the toxins (amins) of the various 
infections lead to such vascular spasm. The high blood pressure 
of vascular disease is therefore compounded of a removable element 
(due to injurious methods of living and the absorption of poison 
from infected areas in the body situated in teeth, tonsils, gall 
bladders, genito-urinary tracts, etc.) and an irremovable element 
(due to scars of an incurable type in the blood vessels themselves) . 

It is time that the old argument of whether blood vessel dis- 
ease leads to high blood pressure or high blood pressure leads to 



884 



(EDEMA AND NEPHRITIS 



vascular " degeneration " were settled, and in favor of the former. 
There is not a particle of physiological, pathological or clinical 
logic behind the second and all evidence is against it. E. C. 
van Leerstjm's 1 work on the subject is definitive. In rabbits 
so operated as to allow of blood pressure readings in perfectly 
uninjured animals he repeated the observations of Nerking and 
Steinbiss that the feeding of horse adrenals and liver led to 
enormous increases in blood pressure (a doubling thereof) for as 
long periods as such feeding was maintained. But even after 
weeks of such treatment the animals showed no signs of vascular 
disease, and their blood pressure fell to normal a few days after 
their abnormal protein diet was cut off. 

The conclusion from such observations is obviously as follows: 
The blood vessel lesions of vascular disease are the pathological 
consequences of embolic infection of the vasavasorum; the 
heightened blood pressure the consequence of the loss in blood 
vessel caliber and elasticity due to the effects of these embolic 
infections plus the effects of more temporarily acting poisons 
derived from the source or sources responsible for the embolic 
infections, or any other sources capable of originating such 
materials. 

§ 4 

The patient before you is at this time better than she was 
some weeks ago, when we first saw her. What was the scheme of 
treatment suggested to her, and how did it work? Obviously the 
fundamental effort in treating patients of this type should be, if 
our analysis has been made correctly, to relieve the vascular 
disease. But as you know, the degenerative and scarring changes 
that occur in vascular disease are not of a reversible kind, and 
consequently not of a variety that can be "cured." Therefore, 
our attention can only be directed toward stopping, if possible, 
the progress of the vascular disease and toward a relief of those 
signs and symptoms which are the expression of this vascular 
disease in the different organs. 

If it is true that the vascular sclerosis brings about a lack of 
circulation through the involved tissues, then, obviously, the 
maintenance of the circulation at its best is a first requisite. It is 

X E. C. van Leersum: Pfliiger's Arch., 142, 377, (1911); Zeitschr. f. exp. 
Path. u. Therap., 11, 2 (1912); Virchow's Arch., 217, 452 (1914). 



APPENDIX 



885 



for this reason that resort to so-called blood pressure lowering 
drugs should not be had too hastily. These may not increase, 
but may actually decrease, the amount of blood going through a 
suffering organ. On the other hand, drugs which increase blocd 
pressure, like digitalis or caffein, may actually prove beneficial. 
This is especially true when the element of cardiac failure, which 
we shall discuss in the next patient, is bringing about a lowering 
of blood pressure in these vascular patients. 

The lack of circulation produced by vascular disease tends to 
be expressed in the involved tissues by an accumulation here of 
carbonic and other acids. The involved tissues will tend, there- 
fore, to become cedematous, which in the case of the brain, for 
example, is manifested in headache. Obviously acids or similar 
substances produced by other methods and elsewhere in the body 
will similarly tend to produce a swelling of the brain. It is there- 
fore of great importance in these vascular patients who may be 
showing only such apparently mild head symptoms as those of 
headache, to discover Yvhatever extracranial factors may be at 
work to produce such substances and to remove them as far as 
may be possible. It is for this reason that the interdiction of hard 
muscular or mental labor, of alcohol, a high protein diet, etc., 
produces such good results. This is simply a method of cutting 
down the sources of acid production in the body. If we add to it a 
continuous administration of alkali in amounts sufficient to keep 
the urine always neutral, we give the different organs involved the 
best possible chances for getting along on the blood supply still 
left to them, and so long as we succeed in so doing our patient 
fares well. - 

§ 5 

But what can we do in our efforts to relieve the vascular disease 
itself? This evidently depends upon what we hold to be the nature 
of vascular disease and its cause. Our text-books teach us that 
hard work, a 1 strenuous life, a high protein diet, lead poisoning 
and many other things are the causes of this trouble. Thus far 
no one has proved by experimental means that any of these things 
really produce an arteriosclerosis, and I think it is a safe gamble 
that no one ever will. I say this because vascular disease, even in 
its extremest grades, remains a spotty affection of the blood vessels. 
In other words, areas of entirely normal blood vessel wall may be 



886 



(EDEMA AND NEPHRITIS 



seen in districts where everything else has suffered heavily. It is 
inconceivable how a soluble poison, like alcohol, for example, 
could circulate for hours, days, or months, through the blood 
vessels and destroy only spots in them. Only a spotty cause can 
be responsible for this spotty destruction. We know at the 
present time only one method by which such a type of destructive 
lesion may be produced and that is through a localization of bac- 
teria in these spots, with secondary destruction of the surrounding 
areas of tissue. And this is, to my mind, what happens in vascular 
disease. The primary changes in vascular disease occur in the 
smallest blood vessels of the body. When they involve a large 
blood vessel, like the aorta, they do so by involving primarily the 
small blood vessels supplying the large one; in other words, the 
vasavasorum. 

It has long been recognized that the spirochete of syphilis is 
capable of settling in these small blood vessels and of producing 
areas of destruction about itself. To it we shall add shortly 
many other types of organisms which we know now to break 
into the blood stream periodically and to give rise to embolic 
infections. Every sufferer from vascular disease must in conse- 
quence be looked over carefully for infected tonsils, teeth, antra, 
ethmoids, hemorrhoids, pelvic organs, prostates, toe nails, etc., 
which might serve as sources of infection to the general blood stream. 

It is because of these views that the patient before you was 
advised to lose the heavily infected teeth that she carried up to a 
few weeks ago. In addition she was put upon alkali, a dietary 
regimen which advised her to eat her vegetables first and then her 
meat — and I must break in here with the remark that eggs, game 
and fowl are just as bad (or just as good) as any other protein 
foods — while a more even life was outlined for her. Her condi- 
tion has improved considerably. Her headaches have practically 
gone ; she has gained in weight and has not had one angina attack 
in several weeks. Her systolic blood pressure has fallen to 200 
and her diastolic to 110. 

§ 6 

What is the prognosis in these patients? It depends, evidently, 
upon the possibility of discovering and of removing the sources of 
infection which we hold to be responsible for the vascular disease, 
and then upon the degree to which the vascular disease has pro- 



APPENDIX 



887 



gressed in some one or all of the vital organs. The ordinary patient 
who is discovered to be a sufferer from so-called chronic interstitial 
nephritis, but who has shown no head symptoms and no heart 
symptoms, is one for whom we can make a prognosis that reads 
"indefinitely good." Causes of death in patients with vascular 
disease run about as follows: one-third die of such things as may 
attack you or me — in other words, the automobile accidents of 
life; of the remainder, one-half die of cardiac failure and the rest 
of accidents to the cerebral circulation, either hemorrhage or an 
oedema of the brain, the latter being usually and wrongly diag- 
nosed as " uremia." 

As may be obvious to you, therefore, a patient who is not and 
has not suffered head symptoms when first seen and who has not 
been dyspneic, or showed a swelling of the feet, or something of 
the sort, is a fairly good risk. Patients showing such symptoms 
may be given a good or bad prognosis, depending upon how much 
of the element in their case is a consequence of irreducible vascular 
disease and how much is due to such added factors as hard work, 
intoxication with alcohol, an anesthesia, or some such thing. 
Where such added elements are missing, as in the very old for 
instance, who may day after day do nothing more strenuous than 
sit in their arm chairs, the prognosis is bad ; in younger individuals, 
unconscious perhaps of the state of their blood vessels, even an 
acute attack of cerebral oedema or something similar does not 
always portend ultimate disaster if they can be tided over the 
attack and then be taught to accept a better mode of life. The 
reasons for this are, of course, clear. In the former type of 
patients, vascular disease must be regarded as almost exclusively 
responsible for the head attack; in the second, the vascular condi- 
tion plays a role, but the added and removable elements have 
played their parts, even more heavily, in the alarming attack which 
may have been the first to direct attention to the more serious and 
irremovable elements. 

For several years I have not seen one of these patients die 
primarily of kidney disease. The normal or so-called " increased" 
urinary output with few casts and little albumin in these cases 
does, it is true, frequently give way to a decreased urinary output 
heavily charged with albumin and casts, but, as I shall show you, 
such change is far more often the consequence of a failing heart 
than of a vascular disease which has progressed to the point of 
blotting out the whole of two kidneys. 



888 



(EDEMA AND NEPHRITIS 



B. The Cardiac Type with Chronic Interstitial Nephritis. 

§ i 

Mr. K., our next patient, is seventy-one years old. He comes 
to us with a history of having had chronic interstitial nephritis and 
high blood pressure for ten years past. In spite of this, he has 
always been well until last spring, when he became somewhat 
short of breath and noticed a swelling of his feet. His physician 
put him to bed for two weeks, during which time his shortness of 
breath and swelling of the feet disappeared, leaving him again 
able to follow his accustomed routine. About two weeks ago he 
observed a return of these two symptoms, and as they became 
steadily worse, he entered the hospital about five days ago. The 
patient informs us that his blood pressure during the past years 
has not varied much from 240 mm. of mercury and that analyses 
of the urine have discovered only traces of albumin. 

On examination of the patient we observe that, because of 
shortness of breath he assumes by preference a half upright posi- 
tion. We have no difficulty in noticing the tortuous and thickened 
blood vessels on the brow, in the neck, in the arms, at the wrists, 
in the femoral regions, in the legs and over the backs of the feet. 
We note also that his pulse beats, as felt at the wrist, are not only 
irregular in rhythm but uneven in intensity. His radial pulse, as 
well as we can count it, is one hundred and twenty-two. Both 
relative and absolute cardiac dullnesses have increased in all 
directions, as I have indicated by the marks upon his chest. The 
booming character of the first sound is impaired and none of the 
heart sounds over the valve areas are pure. There is a marked 
systolic murmur over the mitral area and a systolic and diastolic 
murmur over the aortic. The blood pressure as measured to-day 
is, systolic 161 mm. of mercury, diastolic 88 mm. In examining 
the patient further we find that the liver dullness extends a hand's 
breadth below the costal arch in front and that there is some dull- 
ness over the lower portions of both lungs posteriorly, the extent 
of which I have indicated with pencil lines. There is also a ring 
of dullness low down in the abdomen, evidently due to an accumu- 
lation of fluid. The legs are swollen throughout their length, the 
oedema being most marked in the feet. The nurse informs us that 
there have been only two voidings of urine in the last twenty-four 
hours, amounting in toto to 420 cc. (fourteen ounces). As I show 



APPENDIX 



889 



you in these tubes, this urine is highly acid to methyl red, and 
heavily charged with albumin; microscopically we find it filled with 
granular and hyaline casts. 

§ 2 

While this type of patient is commonly regarded as presenting 
the terminal picture of a chronic interstitial nephritis, I think that 
you will agree with me in holding it more correct to say that he is 
at this time essentially a heart case. For at least ten years he 
has been the victim of vascular disease, which, while it seems in 
this individual to have affected the kidney more than in the pre- 
vious patient, has never interfered sufficiently with his general 
well-being to make him conscious of his diseased state. In fact, 
everything has gone well until last spring when, either because his 
heart muscle tired of the tremendous labor daily demanded of it, 
or because the gradually progressing vascular disease involved 
more extensively his heart muscle, his aortic valves, his aorta, 
or all of these things together, those obvious signs of impairment in 
cardiac efficiency which I have detailed to you, entered to dominate 
the picture. 

Note please that everything we see about him is characteristic 
of heart disease, and nothing justifies our regarding him now as 
suffering primarily from kidney disease. Note also that his blood 
pressure is lower than, from his history, it used to be. It is suffi- 
cient to emphasize that a falling blood pressure in these patients 
with vascular disease and so-called chronic interstitial nephritis, 
when not the consequence of a therapy designed to relieve the 
vascular condition itself , is always a bad sign, for it means a fail- 
ing cardiac efficiency. 

§ 3 

Perhaps some of you would like to insist that this man now 
has more kidney disease than formerly and that his general condi- 
tion has grown worse on this account. His kidney state is worse, 
but for reasons previously discussed not only is this not responsible 
for his general symptoms and signs — his generalized oedema, for 
example — but even the extensive kidney involvement now betrayed 
by his scanty urinary output is not due, in the main, to the vas- 
cular disease which originally affected his kidneys. The present 



» 



890 



(EDEMA AND NEPHRITIS 



picture is almost totally that of a failing heart. In other words, 
this patient is in the same state as the man with heart disease 
whom I showed you earlier in the evening, but the etiology for the 
heart disease in this patient is somewhat different. To show you 
how true this is, it is only necessary to inquire as to what thera- 
peutic schemes aid patients of this type most. In spite of the 
present abnormally high blood pressure, these patients receive most 
benefit from the administration of digitalis, of caffein, of camphor 
and of other drugs which increase blood pressure by increasing 
cardiac activity. As a better circulation is obtained, as the 
products of sub-oxidation are thus better removed and as in this 
general process more oxygen is brought to the kidney, the urinary 
output rises, the albumin diminishes, and, if the heart is not too 
badly affected, these patients may recover completely, as did this 
patient last spring. Were the kidney changes primary and due to 
increased involvement of the kidney by the vascular disease, an 
improvement after cardiac and respiratory stimulation would not 
be so universal. 

§ 4 

We are giving this patient all the alkali he will swallow (he has 
taken sixty grams of sodium bicarbonate in the last twenty-four 
hours) but thus far we have not been able to reduce the acidity of 
his urine to below the turning point of methyl red. We are giving 
him also several doses of digitalis every day and a dose of magne- 
sium sulphate each morning. We shall feel better about him if we 
succeed finally in getting his urine neutral and if time gives indica- 
tion that the aortic and heart muscle lesions are not too severe to 
prevent a return to a more effective forward movement of the blood. 
If such improvement does not take place the outlook is grave. 1 

C. The Cerebral Type with Chronic Interstitial Nephritis 

§ i 

I need not dwell upon that type of chronic interstitial nephritis 
in which cerebral hemorrhage closes the picture. In such cases no 
one ever doubts that the cerebral hemorrhage is secondary to the 

1 The urine of this patient was never made alkaline. The heart rate con- 
tinued high while the intensity of the individual beats gradually diminished 
until, about ten days later, many of them failed to reach the wrist. The 
patient died two weeks after being shown. 



APPENDIX 



891 



vascular disease, so the foolish suggestion is never made that death 
is dependent upon the kidney involvement. There is, however, 
another form of cerebral death in which the death is held to be 
secondary to the kidney disease and I think entirely unjustly so. 
This occurs in those patients for whom has been made a diagnosis 
of chronic interstitial nephritis with high blood pressure and car- 
diac hypertrophy and in whom symptoms alleged to be "uremic" 
close the scene. 

Dr. Gallwey has a patient of this type under his care now, 
but since he has developed a convulsion within the last two hours 
we do not feel justified in bringing him before you. Suffice it to 
say that he is a man forty years old, who for a number of years past 
has shown some casts and albumin in his urine, a systolic blood 
pressure of 165, a diastolic of 102, a certain amount of cardiac 
hypertrophy and at no time any oedema anywhere in the body. 
Three weeks ago he developed drowsy spells, for which he came to 
the hospital. During the past three days it has been difficult to 
rouse him, and this evening he has had a convulsion. Every day 
since he has been in the hospital he has passed about two liters of 
urine and at no time has this showed more than a trace of albumin 
and an occasional cast. The chlorid output, the urea output, etc., 
when due consideration is paid to the character of the food that he 
is consuming, have always been normal. 

§ 2 

The patient presents what the clinicians generally diagnose as 
the " uremia" of chronic interstitial nephritis. After what I 
have told you, I need not emphasize the erroneousness of such a 
view. The primary diagnosis here is again vascular disease which 
has involved different organs in the body. While it has struck the 
kidney to a certain extent, it has largely spared the heart, but it 
has affected severely — and we think disastrously — the circulation 
to the head. What is called uremia in these patients is not secon- 
dary to the loss of kidney function, but is an oedema of the brain 
due to interference with its circulation through the vascular 
disease. Time after time in my experience, as in this case, I 
have seen patients lie for days and weeks, and once even for 
months, in absolute coma, when not one sign pointed to a serious, 
if in fact any. involvement of the kidney. 



892 



(EDEMA AND NEPHRITIS 



What makes the prognosis so bad in these patients is the fact 
that the oedema of the brain (which in itself is not different from 
the oedema produced in such a general intoxication as may be 
incident to pregnancy, or secondary to an anesthetic, starvation, 
or diabetes) is brought about by a vascular disease so marked that 
for its relief we can do practically nothing. Even should we suc- 
ceed in getting this patient out of his coma by the use of alkali, of 
hypertonic salt, of magnesium sulphate, of dextrose, or by the use 
of aU together, our gain is only too commonly likely to prove 
temporary for none of these things influence the vascular disease 
itself which is primarily responsible for the oedema of the brain. 

If I have at all succeeded in making myself clear you will by 
yourselves have come to the conclusion that the mere diagnosis 
"nephritis" can henceforth mean little or nothing. -By itself it 
only states that certain changes essentially colloid-chemical in 
character and produced through the action of acids (and certain 
other substances hke urea, pyridin and the amins), have taken 
or are taking place in the kidney. Having come to such a con- 
clusion, we need to go further and to determine the cause or causes 
which may be behind the abnormal production and accumulation 
of these substances in the kidney. In the list may be found any- 
thing comprised in the practice of medicine from heart disease 
through pregnancy and intoxication with heavy metals : the whole 
category of the acute and chronic, the localized and the general 
infections: the subtleties of nutritional disturbance and mental 
anguish. As I have tried to show you. these things express 
themselves in three main groups of kidney change: first, intox- 
ications originating without or within the kidney and. usually, 
involving the whole of the organ: second, infections of the kidney 
involving either pieces, or when sufficiently extensive, the whole 
of one or both kidneys; third, vascular disease usually affecting 
limited portions of the kidney, though often progressive in type. 

A diagnosis of nephritis must be resolved into its elements ; by 
itself it means no more than a diagnosis reading "headache;" 
"stomach trouble,'' or "dropsy." 



BIBLIOGRAPHY 



This is a list of the publications in which were originally expressed 
the views summed up in running form in the foregoing pages. 

1. Martin H. Fischer: The Physiology of Alimentation, New York 

(1907). 

2. Martin H. Fischer and Gertrude Moore: On the Swelling of 

Fibrin. American Journal of Physiology, 20, 330 (1907). 

3. Martin H. Fischer: On the Analogy between the Absorption of 

Water by Fibrin and by Muscle. Pfliiger's Archiv, 124, 69 (1908). 

4. Martin H. Fischer: Further Experiments on the Swelling of 

Fibrin. Pfliiger's Archiv, 125, 99 (1908). 

5. Martin H. Fischer: The Nature and the Cause of (Edema. Jour- 

nal American Medical Association, 51, 830 (1908). 

6. Martin H. Fischer: On the Swelling of Eyes and the Nature 

of Glaucoma (Preliminary Communication). Pfliiger's Archiv, 
125, 396 (1908). 

7. Martin H. Fischer: On the Swelling of Eyes and the Nature of 

Glaucoma (Second Communication). Pfliiger's Archiv, 127, 1 (1909). 

8. Martin H. Fischer: On Corneal Opacities. Pfliiger's Archiv, 127, 

46 (1909). 

9. Martin H. Fischer: Remarks on a Colloid-Chemical Theory of 

Hemolysis. KoUoid-Zeitschrift, 5, 146 (1909). 

10. Martin H. Fischer and Gertrude Moore: On the Antagonistic 
Action of Neutral Salts on the Swelling of Fibrin in Acids and 
Alkalies. Kolloid-Zeitschrift, 6, 197 (1909). 

11. Martin H. Fischer and Gertrude Moore: On the Passive Con- 
gestion (Edemas of the Kidneys and the Liver. Kolloid-Zeitschrift, 
5, 286 (1909). 

12. Martin H. Fischer: (Edema as a Colloid-Chemical Problem, 
(with Remarks on the General Nature of Water Absorption in the 
Living Organism). Kolloidchemische Beihefte, 1, 93 (1910). 

893 



894 



BIBLIOGRAPHY 



13. Martin H. Fischer: (Edema; a Study of the Physiology and the 
Pathology of Water Absorption by the Living Organism. New 
York (1910). (Also available in German and Russian translation.) 

14. Haywakd G. Thomas and Martin H. Fischer: The Relief of 
Glaucoma through Subconjunctival Injections of Sodium Citrate. 
Annals of Ophthalmology, 19, 40 (1910.) 

15. Martin H. Fischer: On the Nature of Cloudy Swelling. 
KoUoid-Zeitschrift, 8, 159 (1911). 

16. Martin H. Fischer: Further Remarks on the Colloid-Chemical 
Analysis of Nephritis. KoUoid-Zeitschrift, 8, 201 (1-911). 

17. Martin H. Fischer: Contributions to a Colloid-Chemical Analysis 
of Absorption and Secretion. (Absorption from the Peritoneal 
Cavity). Kolloidchemische Beihefte, 2, 304 (1911). Reprinted 
in English in Cincinnati Lancet-Clinic, 107, 684 and 702 (1912). 

18. Martin H. Fischer: Some Practical Points in the Treatment of 
Nephritis. Ohio State Medical Journal, 7, 400 (1911). 

19. Martin H. Fischer: On the Nature, Cause, and Relief of Glau- 
coma. Trans. Amer. Acad. Ophth. Oto.-laryn., 193 (1911). 

- 20. Martin H. Fischer: Nephritis; An Experimental and Critical 
Study of Its Nature, Cause and the Principles of Its Relief. New 
York (1912). (Also available in German and Russian translation.) 

21. William H. Strietmann and Martin H. Fischer: On the Con- 
traction of Catgut and the Theory of Muscular Contraction. 
KoUoid-Zeitschrift, 10, 65, (1912). Reprinted in English in Cin- 
cinnati Lancet-Clinic, 108, 205 (1912). 

22. Marian O. Hooker and Martin H. Fischer: On the Absorption 
of Water by Nerve Tissue. KoUoid-Zeitschrift, 10, 283 (1912). 

23. James J. Hogan and Martin H. Fischer: On the Theory and 
Practice of Perfusion. Kolloidchemische Beihefte, 3, 385 (1912). 

24. Martin H. Fischer: A Response to Some Criticisms of the 
Colloid-Chemical Theory of Water Absorption by Protoplasm. 
Biochemical Bulletin, 1, 444 (1912). 

25. Martin H. Fischer: A Further Response to Some Criticisms of the 
Colloid-Chemical Theory of Water Absorption by Protoplasm. 
Journal American Medical Association, 59, 1429 (1912). 

26. Martin H. Fischer : Further Remarks on the Treatment of Neph- 
ritis. Trans. Association American Physicians, 27, 595 (1912). 

27. Martin H. Fischer: Physical Chemistry in Pharmacology and 
Therapeutics. Section in F. Forchheimer's Therapeusis of Inter- 
nal Diseases, 1, 1, New York (1913). 

28. Martin H. Fischer: A Third Response to Some Criticisms of the 
Colloid-Chemical Theory of Water Absorption by Protoplasm. 
Journal American Medical Association, 60, 348 (1913). 



BIBLIOGRAPHY 



895 



29. Martin H. Fischer: Further Remarks on the Treatment of Ne- 
phritis and Allied Conditions. Kolloidchemische Beihefte, 4, 343 
(1913). 

30. Martin H. Fischer: The Treatment of Nephritis and Allied Con- 
ditions. Journal American Medical Association, 60, 1682 (1913). 

31. Martin H. Fischer and Anne Sykes: On the Colloid-Chemical 
Action of the Diuretic Salts. (Preliminary Communication), 
Science, 37, 845 (1913). 

32. Martin H. Fischer and Anne Sykes: Non-Electrolytes and the 
Colloid-Chemical Theory of Water Absorption. Science, 38, 486 
(1913). 

33. Martin H. Fischer and Anne Sykes: On the Colloid-Chemical 
Action of the Diuretic Salts. Kolloid-Zeitschrift, 13, 112 (1913). 

34. Martin H. Fischer: On the Nature, Cause and Relief of Nephritis, 
Journal Medical Society, New Jersey, 11, 116 (1914). 

35. Martin H. Fischer and Anne Sykes: On the Effect of Some Non- 
Electrolytes on the Swelling of Protein. Kolloid-Zeitschrift, 14, 
215 (1914). 

36. Martin H. Fischer and Anne Sykes: On the Colloid-Chemistry of 
Sugar Diuresis. Kolloid-Zeitschrift, 14, 223 (1914). 

37. Martin H. Fischer: On the Relation between Chlorid Retention, 
(Edema and "Acidosis." Journal American Medical Association, 
64, 325 (1915). Also Kolloid-Zeitschrift, 16, 106 (1915). 

38. Martin H. Fischer and Anne Sykes: On the Non-Acid and Non- 
Alkaline Hydration of Protein. Kolloid-Zeitschrift, 16, 129 (1915). 

39. Martin H. Fischer: The Relation of Mouth Infection to Systemic 
Disease. Dental Summary, 35, 607 (1915). Also Lancet-Clinic, 
114, 124 (1915). 

40. Martin H. Fischer: On the Life of Animals with Suppressed 
Kidney Function. Science, 41, 584 (1915). 

41. Martin H. Fischer: On Hydration and "Solution" in Gelatin. 
Science, 42, 223 (1915). 

42. Martin H. Fischer: On Hydration and "Solution" in Gelatin. 
Kolloid-Zeitschrift, 17, 1 (1915). 

43. Martin H. Fischer and Marian 0. Hooker: On the Physical 
Chemistry of Emulsions and its Bearing upon Physiological and 
Pathological Problems, Science, 43, 468 (1916). 

44. Martin H. Fischer and Marian 0. Hooker: On the Making and 
Breaking of Emulsions. Kolloid-Zeitschrift, 18, 129 (1916). 

45. Martin H. Fischer and Marian O. Hooker: On the Analogy 
between the Behavior of Emulsions and the Behavior of Fats in 
Protoplasm. Kolloid-Zeitschrift, 18, 242 (1916). 

46. Martin H. Fischer and Marian O. Hooker: The Mimicry of 
Mucoid Secretions. Kolloid-Zeitschrift, 19, 88 (1916). 



896 



BIBLIOGRAPHY 



47. Martin H. Fischer and Marian 0. Hooker: On the Mimicry of 
Some Anatomical Structures. Kolloid-Zeitschrift, 19, 220 (1916). 

48. Martin H. Fischer: Diagnosis, Prognosis and Treatment in Ne- 
phritis. Lancet-Clinic, 115, 419 and 443 (1915). Also Kolloid- 
chemische Beihefte, 9, 138 (1917). 

49. Martin H. Fischer: The Principles of Treatment in Nephritis. 
Journal Tennessee State Medical Association, April 15, 1916. 

50. Martin H. Fischer: The Classification and Treatment of the 
Nephritides. Journal-Lancet, 36, 371 (1916). Also Journal Medical 
Society of New Jersey, 13, 555 (1916); Pennsylvania Medical 
Journal, 21, 236 (1918). 

51. Martin H. Fischer and Marian 0. Hooker: Fats and Fatty 
Degeneration, New York (1917). 

52. Martin H. Fischer, Marian 0. Hooker, Martin Benzinger and 
Ward D.Coffman: On the Swelling and "Solution" of Protein in 
Polybasic Acids and their Salts. Science, 46, 189 (1917). 

53. Martin H. Fischer 'and Marian 0. Hooker: On the Swelling of 
Gelatin in Polybasic Acids and their Salts. Journal American 
Chemical Society, 40, 272 (1918). 

54. Martin H. Fischer and Martin Benzinger: On the Swelling of 
Fibrin in Polybasic Acids and their Salts. Journal American 
Chemical Society, 40, 292 (1918). 

55. Martin H. Fischer and Ward D. Coffman: On the Liquefaction 
or " Solution" of Gelatin in Polybasic Acids and their Salts. Journal 
American Chemical Society, 40, 303 (1918). 

56. Martin H. Fischer: The Colloidal-Chemical Theory of Water 
Absorption: A Fifth Response to Some Criticisms. Journal 
American Chemical Society, 40, 862 (1918). 

57. Martin H. Fischer and Marian O. Hooker: "Trench Nephritis." 
International Association of Medical Museums, Bulletin No. 7, 174 
(1918). 

58. Martin H. Fischer and Marian 0. Hooker: Ternary Systems and 
the Behavior of Protoplasm. Science, 48, 143 (1918). 

59. Martin H. Fischer: "Fats and Fatty Degeneration": A Response 
to Book Reviews by Bancroft and Clowes. Science, 48, 194 (1918). 

60. Martin H. Fischer: Further Studies in Colloid Chemistry and 
Soap. Science, 49, 615 (1919). 

61. Martin H. Fischer: Practical Urinalytic Methods. Chapter in 
"Practice of Medicine," edited by Theodore Tice, New York (1919). 

62. Martin H. Fischer and Marian O. Hooker: On the ^dration 
Capacity of Some Pure Soaps. Chemical Engineer, 27, 155 (1919). 

63. Martin H. Fischer: Non-Aqueous Lyophilic Soap Colloids. 
Chemical Engineer, 27, 184 (1919). 



BIBLIOGRAPHY 



897 



64. Martin H. Fischer and Marian 0. Hooker: On the Colloid Chem- 
istry of Potassium Oleate. Chemical Engineer, 27, 223 and 253 
(1919). 

65. Martin H. Fischer: On the Reaction of Soaps to Indicators. 
Chemical Engineer, 27, 271 (1919). 

66. Martin H. Fischer: A Second Model Illustrating Some Phases of 
Urinarv Secretion. Journal Laboratory and Clinical Medicine, 5, 

- 207 (1920). 

67. Marian 0. Hooker and Martin H. Fischer: On the Swelling and 
"Solution" of Aleuronat. Kolloid-Zeitschrift, 26, 49 (1920). 

68. Martin H. Fischer and George D. McLaughlin: A Third Model 
Illustrating Some Phases of Urinary Secretion. Journal Laboratory 
and Chemical Medicine, 5, 352 (1920). 



AUTHOR INDEX 



A 

Abderhalden, Emil, 670 

Adams, L. P., 705 

Alberran, J., 765 

Alden, B. F., 416, 417, 418, 419 

Alexander, Jerome, 44 

Allen, G. M., 722, 723 

Araki, Trasaburo, 235, 236, 239, 

245, 273, 487, 492, 496, 497, 499, 

500 

Arnold, Julius, 555 
Arnold, Rudolf, 179, 470 
Ash, 850 

B 

Badt, 487 

Baehr, Edmund M., 518, 629, 692, 

721, 722, 723, 752 
Baetjer, W. A., 637, 641 
Bainbridge, 423 
Balcar, J. O., 694 
Ball, Jau Don, 732 
Ballenger, E. G., 672, 792 
Barcroft, J., 358, 381, 383, 487 
Bardeen, 481 
Basham, 678 
Bass, C. C, 841, 846 
Bauer, 267 
Bauer, J., 179, 191 
Bayliss, W. M., 423, 425, 518 
Bechhold, H./ 44, 179 
Bell, Albert J., 792 
Belt, A. E., 730 
Benzinger, Martin, 602 
Berghausen, Oscar, 445, 498, 659 
Beutner, R„ 468 

Billings, Frank, 635, 755, 816, 827, 

832, 834 
Blatherwick, N. R., 670 
Blechmann, G., 424 
Bock, C., 695 
Bolduan, 212 



Borowikow, G. A., 450 

Botazzi, Phil., 807 

Bowman, W., 326, 359, 380, 484, 540 

Breschot, 424 

Brieger, 267 

Bright, Richard, 217, 218, 496, 532, 

636, 749, 826, 831, 835, 878 
Brodie, T. G., 358, 381, 383 
Brooks, Clyde, 836 
Brown, Herbert, 792 
Brucke, E., 152 , 
Buchner, 499 
Bugarsky, S., 477 
Bullowa, J. G. M., 44, 179 
Bunge, G. von, 501, 670 
Burton-Opitz, R., 625 

C 

Callahan, 844 
Calvin, J. W.,129, 133 
Campbell, Elizabeth, 699, 725 
Cannon, W. B., 423, 424, 731 
Carrell, 733 
Cheyne, 685, 752, 859 
Chiari, O., 733 
Claret, 424 
Clark, W. A., 707, 712 
Clark, W. M., 771 
Clarke, J. Michell, 792 
Coffey, W. B., 419, 420 
Coffman, Ward D., 377, 597 
Cohn, E. J., 133 

Cohnheim, Julius, 269, 277, 279, 280, 
286, 287, 288, 541, 555, 859 

Cohnheim, Otto, 218, 219, 299, 311, 
323, 477 

Cole, S. W., 779 

Colwell, E. M., 424 

Conzen, F., 718 

Cotton, 487 

Creighton, 770 

Crile, George W., 788 

899 



900 AUTHOR 

Cullis, W. C, 381 
Cummer, W. E., 850 
Curdts, C. E., 715 
Cushing, Harvey, 732 
Cushny, A. R., 311, 312, 381 
Cutler, E. C, 732 
Czapek, F., 449 

D 

Dakin, 733 

Davenport, C. B., 446, 447 
Davis, D. J., 756 
Dernoschek, A., 402 
Dick, George F., 826 
Dick, Gladys R., 826 

DlEULAFOY, G., 718 

Dreser, H., 480, 481, 482, 483, 484, 

486, 646 
Driesch, 446 
Duclaux, 499 
Dunham, H. K., 701 
Dunn, A. D., 753, 792, 882 
Durig, A., 193, 198 

E 

Eckstein, Gustav, Jr., 837, 844 
Edlefsen, G., 493 
Ehrlich, Paul, 212 
Eichberg, J. H., 703 
Eijkman, C, 153, 219, 234 
Elder, Frank R., 265 
Elder, Omar F., 672, 792 
Elliot, 423 
Emmerling, O., 267 
Engelmann, T. W., 452, 460, 463 
Erlenmeyer, 509 
Ervin, D. M., 754 
Esbach, 494, 510, 715, 716 
Eustis, Allan, 267 
Evans, 487 
Ewald, A., 235 

F 

Fairhall, L. T., 760 
Farkas, G., 476 
Fiaschi, P., 424 
Fick, Adolph, 323 
Fihe, C. C, 711, 732 

FlNDLAY, 770 

Fischer, Martin H., 44, 47, 49, 50, 
51, 52, 57, 61, 70, 73, 99, 133, 



INDEX 

146, 148, 155, 169, 179, 191, 203, 
266, 270, 274, 331, 339, 349, 356, 
357, 363, 371, 377, 379, 380, 381, 
383, 393, 400, 401, 403, 438, 451, 
465, 469, 498, 508, 519, 526, 527, 
540, 567, 574, 596, 597, 602, 659, 
680, 695, 728, 740, 746, 775, 779, 
792, 798, 807, 852 

Fletcher, M. H., 818 

Fletcher, W. M., 462, 492, 788 

FORCHHEIMER, F., 816 
FORSTER, J., 501 

Fourquier, G., 789 
Fowler, C. C, 760 
Fraenkel, P., 476, 718 
Fraser, John, 424 
Frerichs, F. T., 533, 718 
Freundlich, H., 50 
Frey, Ernst, 364, 365 
Friedlander, 279 
Friedlander, J., 52, 54 
Frolich, Theodor, 237, 238 
Fuchs, Ernst, 795 
Furth, von, 470 



G 

Gallwey, 891 
Garnier, 333, 406 
Gedroiz, K., 179, 450 
Geier, Otto P., 702 
Genth, 759 
Geraghty, J. T., 762 
Germans, H., 844 
Gettler, A. O., 670 
Gies, W. J., 262, 265, 285 
Gilbert, 804 
Glaesgen, 718 
Glaser, Fritz, 771 
Goodridge, F. G., 285 

GOPPELSROEDER, F., 373 

Gottlieb, R., 366 
Graefe, von, 795 
Graham, Evarts, 739, 789 
Graham, Thomas, 44, 45, 283, 371, 

372, 376, 505, 507 
Graves, 827 

G rinnan, George J., 792 

Grober, J., 470 

Grutzner, P., 483, 485 

Gryns, 197, 234 

Gurber, August, 153, 219, 315 

Guthrie, C. C, 424, 730 



AUTHOR INDEX 



901 



H 

Haake, B., 363 

Halliburton, 551 

Hamburger, H. J., 153, 194, 197, 

219, 234, 275, 276, 299, 302, 311, 

315, 316, 317, 324, 431, 432, 433, 

542, 543, 549 
Hamilton, N. A., 708, 714 
Hammarsten, O., 411, 551 
Handovsky, Hans, 115, 146, 296, 

402, 465, 554, 624 
Hardy, W. B., 52, 133, 146, 507, 624 
Hart, E. B., 551 
Hartzell, T. B., 636, 831 
Hauch. 536 
Hawk, P. B., 760 
Hedin, 197 

Heidenhain, R., 299, 311, 318, 323, 
359, 380, 480, 483, 484, 485, 486, 
505, 646 

Heilner, E., 358 

Heller, 493 

Henderson, L. J., 133, 476, 567, 

614, 769, 770, 771, 791 
Henderson, Yandell, 421, 422, 

487, 790 
Henle, J., 327 
Henrici, T., 636, 831 
Hermann, L., 462, 465, 466 
Herrmann, Max, 499, 659 
Herter, E., 279 
Hinman, 850 
Hieokawa Waichi, 275 
His, 835 

Hober, Rudolf, 193,1 197, 203, 
299, 311, 312, 441, 451, 476, 477, 
478 

Hoefft, F. vois, 488 

Hoesslin, R. VON, 718 

hoeve, van der, 804 

Hoff, van' t, 197 

Hoffmann, F. A., 695 

Hofmeister, F., 75, 77, 110, 145, 

151, 153, 154, 193, 311, 318, 324, 

331, 356, 463, 464 
Hogan, James J., 311, 356, 403, 416, 

417, 420, 424, 425, 636, 694, 696, 

700, 705, 731, 733, 740, 743, 785, 

792 

Holmes, C. R., 723 
Holst, Axtel, 237, 238 
Holt, O. P, 723 

Hooker, Marian O., 51, 57, 133, 



148, 179, 191, 203, 274, 381, 508, 
526, 540, 567, 596, 728, 732 

Hopkins, F. G., 462, 492, 788 

Hoppe-Seyler, F., 235, 236, 273, 
492, 497, 499, 742 

Hunter, William, 818 

Huxley, T. H., 446 

Hyatt, Thaddeus, 844 

I 

Iras aw a, T., 497 
Irons, Ernest E., 756 
Isaacs, Raphael, 763 

J 

Jackson, Lelia, 636, 826 

Jaksch, R. von, 236, 239, 479, 497 

Janeway, Theodore C, 791 

Januschke, 733 

Johns, F. M., 841, 846 

Jolles, A., 239 * 

Jones, Lauder W., 771 

K 

Kahlenberg, Louis, 449 
Karell, 743 
Kennedy, R. D., 498 
Kiely, W. E., 702 
Kiliani, H., 499 
Kiss, Julius, 440, 441 
Kite, G. L., 287 
Klemensiewicz, Rudolf, 285 
Klose, H., 179 
Koeppe, 197, 198, 440 
Kopetzky, S. J., 731 
Koppel, Max, 567, 770 
Korner, M., 285 
Kovesi, G., 311 
Kraus, F., 479 
Kuder, W. S., 732, 742 

L 

Landsteiner, Karl, 542 
Laqueur, E., 551 
Laub, 487 

Lazarus-Barlow, W. S., 219 
LeCount, E. R., 636, 755, 826 
Leersum, E. C. van, 787, 884 
Lenk, 470 

Leube, W. von, 493, 718 



902 



AUTHOR INDEX 



Leubuscher, 316 
Lewis, 487 

Lichtheim, Ludwig, 218, 286 

LlEBERMANN, L., 477 

Liesegang, Raphael Ed., 179 
Limbeck, C. von, 153, 219, 234, 315, 
363 

LlNDER, 372 

Litchfield, Lawrence, 730, 791, 
792 

Lloyd, John Uri, 373 
Locke, 404, 406 

Loeb, Jacques, 152, 153, 197, 198, 

219, 220, 433, 448, 468 
Lohse, J. L., 733 
Long, J. D., 733 
Lowit, M., 277 
Lowenberg, H., 792 
Luciani, Luigi, 237 
Ludwig, Carl, 318, 359, 380, 484 
Luers, H., 133 
Lunin, N., 501, 670 



M 

Magnus, R., 288, 289, 336, 363, 366 
Majors, E. A., 710 
Maly, Richard, 371, 379 
Mandel, J. A., 551 
Mann, F. C, 424 
Manouelin, Y., 636 
Marchand, Felix, 285, 721 
Mathews, A. P., 52 
MacDougal, D. T., 450, 451 
MacNider, William DeB., 728, 
792 

McDougall, William, 462, 463, 

466, 467, 468 
McKibben, Paul S., 732 
McKim, Gordon F., 785, 786, 792 
McLaughlin, George D., 148, 380 
Meigs, Edward B., 461, 462, 463, 

467, 468 
Meisenheimer, 499 
Meloy, J. C., 239 
Meltzer, S. J., 276 
Mendel, E., 235, 497 
Mendel, L. B., 314 
Mering, von, 314 

Meyer, Hans, 208, 438, 440, 487, 
741 

Miller, Edgar G., Jr., 265 



Miller, Joseph L., 720 

Mithoefer, William, 785 

Moore, A. R., 792 

Moore, Gertrude, 61, 245, 270 

Munk, J., 302, 444 

Munzer, E., 487, 497 

N 

Nasse, O., 152 

Nathansohn, A., 203 

Nef, J. U., 499 

Neilson, C. H., 409, 424 

Nerking, 884 

Nesbett, Norman B., 850 

Neumann, W., 759 

Newburgh, L. H., 567, 720, 721, 

769, 770, 791 
Nicloux, Maurice, 789 
Noorden, C. von, 493 
Noyes, A. A., 49, 50, 771 
Nussbaum, M., 480, 483, 646 



O'Connor, 852 
Oliver, Wade W., 201 
Oppenheim, H., 239, 759 
Orlow, 302 
Osborne, W. A., 551 
Osler, 718 

Ostwald, Wolfgang, 44, 47, 49, 
50, 51, 52, 54, 60, 75, 76, 77, 81, 
133, 194, 204, 208, 219, 243, 262, 
283, 371, 402, 564, 797 

Overton, E., 153, 194, 197, 198, 
200, 201, 202, 203, 288, 299, 433 ; 
435, 436, 437, 438, 440, 468, 641 



P 

Paine, A., 822 

Palma, P., 487, 497 

Palmer, W. W., 567, 769, 770, 791 

Pauli, Wolfgang, 75, 146, 194, 296, 

402, 433, 440, 465, 470, 551, 554, 

624 

Pauson, Charles A., 785 
Peiper, E., 479 
Pelet-Jolivet, L., 212 
Pemsel, W., 477 
Perrin, J., 50 

Pfeffer, W., 193, 196, 197, 200, 202, 
433, 437 



AUTHOR INDEX 903 



Picton, H., 372 
Pieck, C. G., 721 
Pokrowsky, 279 
Ponfick, E., 336 
Post, W. E., 673, 756 
Potzl, O., 179 
Powell, Alvin, 786 
Poynton, F. J., 822 
Priestley, J. T., 627 
Przibram, E., 179 

R 

Ravine, William, 497 
Recklinghausen, von, 555 
Reemelin, Edward B., 763 
Regeczy, E. von, 507 
Reid, E. Waymouth, 299, 311, 316, 

322, 323 
Rhorer, Ludwig von, 477 
Richards, D. N., 418 
Rindfleisch, E., 541 
Ringer. 260, 261, 404, 458, 461, 653, 

654, 655, 730 
Roach, 850 

Robertson, T. B., 442, 477, 551 
Roger, H., 333, 406 
Romberg, E., 718 

Rosenow, Edward C, 635, 755, 822, 
823, 824, 825, 827, 828, 832, 846, 
856 

Rosenstein, 302, 718 
Rothmund, V., 52, 54 
Rowntree, L. G., 762 
Rulon, S. A., 760 
Rumpf, W. H., 479 
Russ, W. B., 785 
Ryffel, 487 

Rysselberghe, van, 451 
S 

Sachs, 448 
Sackur, O., 551 
Sahlbom, N., 373 
Sahli, H., 277 
Saiki, 314 
Salant, W., 673 
Salm, Eduard, 771 
Salus, G., 531 
Sansum, W. D., 694, 804 
Scalinci, N., 807 
Schade, 499 
Scheltema, M. W., 718 



Schiotz, 805 

Schloss, Ernst, 670 

Schmidt, C, 302 

Schmidter, W. C, 701 

Schorr, Karl, 146, 402, 465, 554 

Schroeder, P. VON, 146, 624 

schuller, a., 179 
Schutzenberger, 499 
Schwarz, O., 762, 763 
Sellards, A. W., 488 
Senator, 718 
Sherman, H. C, 670 
Sive, B., 771 
Sjoquist, J., 477 
Slyke, L. L. van, 551 
Smith, Dudley, 706 
Smith, E. O., 792 
Smith, H. P., 730 
Smith, Priestley, 795 
Sollman, Torald, 363 
Sorenson, S. P. L., 770, 771 
Southworth, Rufus, 792 
Spear, E. B., 44, 47 
Spiro, K, 75, 79, 275, 363, 477 
Spoehr, H. A., 451 
Stahl, S. S., 714 

Starling, E. H., 299, 301, 366, 423, 

424, 518 
Steinbiss, 884 
Stokes, 685. 752, 859 
Stone, W. J., 753 
Strassburg, G., 235, 742 
Straub, H., 381, 383 
Strietmann, William H., 451 
Succi, 237 
Sutton, G. E., 424 
Sykes, Anne, 70, 73, 99, 266, 339, 

349, 356 

T 

Tate, Magnus A., 792 
Taylor, N. B., 733 
Taylor, W. H., 733 
Terray, P. von, 496 
Thomas, Hayward G., 785, 798, 800, 
802 

Thompson, G., 497 

Tice, Theodore, 746 y 

Tolman, Richard C., 402 

Tracy, Grover, 265 
I Traube, Isador, 179 
I Traube, Moritz, 196, 242 



904 



AUTHOR INDEX 



True, Rodney, 449 
Tsuchiya, 494 
Tubby, 301 
Tuechter, J. L., 702 



Underbill, F. P., 673 
Upson, Fred W., 129, 133 



V 

VlERORDT, 302 

Yirchow, R., 500, 540 
Yoigt, H., 179 
Yoit, 311 

Yries, Hugo de, 196, 197, 202, 433 



W 

Walker, C. A., 419, 420 
Wallace, G. B., 311, 312 
Webster, R. W., 153, 197, 198 . 
Weed, Lewis H., 732 
Weigert, 533 

Weimarn, P. P. von, 46, 51 
Weiske, H., 237, 673 



Weiss, H. B., 727, 792 
Welch, William H., 276, 277 
Wells, H. G,. 673 
Wharton, 206 

Wherry, William B., 756, 820, 821 f 

822, 828, 829, 845 
Whipple, G. H., 730 
Widal, 743 
Wilder, R. M., 804 
Winternitz. M. C., 239 
Wittich. W. von, 324 
Wolf, 487 

Wood. T. B.. 133, 507 
Woodyatt. R. T., 500, 694, 756, 804, 
827, 873 

Woolley, Paul, G., 445, 554, 734,, 
792 

Wright, A. E., 237, 733 
Wymore, W. W., 863 

Z 

Zangger, Heinrich, 212 
Ziegler, C., 285 

Zillessen, Hermann, 235, 236, 239, 

273, 496, 499 
Zsigmondy, Richard, 44, 47 
Zuntz, 501 



SUBJECT INDEX 



A 

Absorbing Membrane, physical chemistry of, 297. 

Absorption, of dissolved substances by protoplasm, 206; of blood from 
peritoneal cavity, 305, 740; of salt solutions from peritoneal cavity, 
306; of non-electrolytes from peritoneal cavity, 308; of acid and alkali 
from peritoneal cavity, 309; in dead animals, 310; from gastro-intes- 
tinal tract, 311; theory of, 315; of dissolved substances from peri- 
toneum and alimentary tract, 315, 317; filtration theory of, 316; osmotic 
theory of, 317; physiological and vitalistic theories of, 317, 321; selec- 
tive, 319; of hypertonic, hypotonic and isotonic solutions, 319, 320; of 
blood from gastro-intestinal tract, 323. 
See also, Absorption of Water. 

Absorption of Water, by fibrin, 61, 71; by gelatin, 75; by gluten, 129; 
by muscle, 151, 433; by eye, 169; general problem of, 293; in complex 
organism, 293; from peritoneal cavity, 299; from gastro-intestinal 
tract, 312; by spermatozoa, 430; by epithelial cells, 430; by white 
blood corpuscles, 430. 

Acetone, and gelatin, 110; and nephritis, 499, 670; compounds, 778. 

Acetone Bodies in nephritis, 670. 

Acid, and fibrin, 61, 509; salt antagonism to, 64; and gelatin, 76, 514; and 
aleuronat, 134; and muscle, 154; and eye, 170; and nervous tissue, 180; 
accumulation of, in oedema, 232, 233; in infections, 267; and pulmonary 
oedema, 279; absorption of, from peritoneal cavity, 309; action of, on 
spermatozoa, epithelial cells and white blood corpuscles, 432; formation 
of, in plants, 451; and catgut, 453; role of, in muscle contraction, 466; 
accumulation of, in nephritis, 475; injection of, and nephritis following, 
489; and swelling and " solution " of gelatin, 520; and cloudy swelling, 
544; and secretion of dissolved substances, 642; and staining of colloids, 
644; in diet of nephritic, 669. 

AciD-FORMfNG elements in food, 670. 

Acid Fuchsin, and staining of kidney, 481. 

Acid Intoxication, holding of breath as index of, 790. 

Acidity of normal and abnormal urine, 478, 766, 861; measurements of, in 
urine, 765. 

Acidosis, 778; definition of, 780; in nephritis, 780; and respiration, 790. 
Adequacy, of colloid-chemical theory of absorption, 204. 
Adsorbent, 210. 

Adsorption, and distribution, 210; role of, in hemolysis, 312. 
After-treatment, 788. 
Agar-agar, 313. 

905 



906 



SUBJECT INDEX 



Albumin Test, 147. 

Albuminuria, test for, 147; as " solution " phenomena, 379; or newborn, 500; 

general remarks on, 504; theories of, 505; solution theory of, 506, 507, 

significance of, 747. 

See also, Nephritis. 
Albuminuric Retinitis, 631. 

Alcohols, and fibrin, 70; and gelatin, 100, 105, 106, 109; and muscle, lo4, 
436; and eye, 177; and nervous tissue, 188; absorption of, from peri- 
toneal cavity, 308; and urinary secretion, 361, 362; and nephritis, 
499; in nephritic diet, 670. 

Aleuronat, 133; and acids, 134; and alkalies, 138; and non-electrolytes, 139; 
and salts, 139. 

Alkali, and fibrin, 63; salt antagonism to, 64; and gelatin, 79; and aleuronat, 
138; and muscle, 156; and eye, 172; and oedema, 266; absorption of, 
from peritoneal cavity, 309; action of, on spermatozoa, epithelial cells, 
and white blood corpuscles, 432; and production of nephritis, 502; and 
swelling and "solution" of gelatin, 521; and cloudy swelling, 547 rf , 
in albuminuria of hard work, 665; in treatment of nephritis, 668, 671, 718; 
and rule for giving, 693; in heart disease, 720; in other conditions than 
nephritis, 731, 734; in high blood pressure, 753; in preparation of surgical 
patients, 785. 

Alkalinity, of blood in oedema, 236. 

Alveolar Abscess, and focal infection, 831. 

Amins, and fibrin, 73; and swelling of gelatin, 115, 128; and oedema, 266; 

in infections, 267, and shock, 425. 
Amino-acids, 396. 
Amino-fatty-acids, 396. 

Ammonia, excretion of, in nephritis, 487; determination of, in nephritis, 774, 
778. 

Amphoteric Proteins, 150. 
Ampoules, 688. 

Amyl Nitrite, and nephritis, 499. 

Analogy, between protein and protoplasmic swelling, 151; between pro- 
tein and muscle swelling, 151; between soap and muscle, 152; between 
protein and eye swelling, 169; between protein and nervous tissue 
swelling, 178; between catgut and muscle contraction, 461. 

Analysis, by dialysis, 45. 

Anasarca, 237. 

Anemia, pernicious, and oedema, 236; and nephritis, 496. 

Anesthetics, and secretion, 361; and nephritis, 499, 696; protection against 

after-effects of, 786; local, 789; poisonous effects of, 789. 
Angina Pectoris, 882. 
Angioneurotic (Edema, 731. 

Antagonism, between neutral salts and acid and alkali, 64, 81, 129, 146; 

between urea and sugars, 74, 119, 120; between pyridin and sugars, 

75, 123, 124; history of discovery of, 431. 
Ante-operative Care, 784. 

Apparatus, for injection of sodium carbonate-sodium chlorid solution, 688, 

691, 692. 
Appendicitis, 828. 

Arsenic, and oedema, 245; and nephritis, 499, 731; oedema-producing effects 

of, 789; avoidance of after-effects from, 789. 
Arteriosclerosis, see Vascular Disease. 



SUBJECT INDEX 



907 



Ascites, 740, 742. 

Ascitic Fluid, transfusion of, 416. 

Asphyxial nephritis, 498, 647; treatment of, 649, 659. 

Asthma, 267; bronchial, 731. 

Atheroma, see Vascular Disease. 

Athletes, and nephritis, 493; relief of albuminuria in, 665. 
Atropin, 787; and urinary secretion, 361; and lymph formation, 398. 

B 

Baehr Apparatus, 691. 
Base-forming elements in food, 670. 
Basham's Mixture, 677. 
Beer, 676. 

Betaimidazolylethylamin, 268. 

Bibliography of colloid-chemical theory of water absorption, 893. 

Biology, importance of colloid hydration in, 193; and colloid-chemical 

theory of water absorption, 429. 
Blindness, 687. 

Blood, alkalinity of, in oedema, 236; physical chemistry of, 298, 327; 
compared with lymph, 302; composition of, 302; absorption of, from 
peritoneal cavity, 305, 316, 740; changes of corpuscles in arterial and 
venous, 315; gastro-intestinal absorption of, 323; effect of, on urinary 
secretion, 336; why it remains in the blood vessels, 403; intravenous 
injection of, 405, 416; neutrality of, 476; hydroxyl and hydrogen ions 
in, 477; decreased alkalinity of, in nephritis, 479. 

Blood Pressure, and theory of oedema, 271; decrease of, as cause of oedema, 
271; and urinary secretion, 359; treatment of abnormally low, 415; 
increased, not due to kidney loss, 615; benefits of increased, 625; 
increase of, in general intoxications, 752; and bronchial oedema, 752; 
treatment of increased, with alkali, 753; increased, and vascular disease, 
884.- 

Blood Serum, intravenous injection of, 407, 416. 

Brain (Edema, 732, 867; in sulphuric acid poisoning, 721; treatment of, 721, 

732; different types of, 731; in nephritis, 752. 
Breath, foul, 845. 
Bridges, 850. 

Bright's Disease, see Nephritis. 

British Medical Research Committee, 423. 

Bronchial Arteries, 278, 731. 

Bronchial Asthma, 731. 

Buffer Salts, 567. 

C 

Cachexia, oedema of, 287. 
Caffein, and urinary secretion, 362. 
Calcium Salts, in oedema, 670. 
Calomel, in nephritis, 672. 
Cane Sugar, see Saccharose. 
Cannula, 690. 

Capacity, gelation, 59; hydration, 59; swelling, 59; solvation, 59. 
Capillary Analysis, 373. 
Carbon, 210. 

Carbon Monoxid, nephritis in poisoning by, 497. 



908 



SUBJECT INDEX 



Carbonates, and swelling of gelatin, 592; and " solution " of gelatin, 601; 

and swelling of fibrin, 604. 
Carmin, and fibrin, 442. 
Carrell-Dakin Solution, 733. 

Casein, intravenous injection of, 411, 413; physico-chemical behavior of, 
551. 

Cases, of shock, 417; of nephritis, 551; of chronic interstitial nephritis, 703; 

of glaucoma, 800; of focal infection, 834. 
Casts, origin of, 560; types of, 561; significance of, 748. 
Catgut, contraction of, 452; effect of acid on, 453; effect of time on, 454; 

residual contraction in, 455; effect of salts on, 456; effect of Ringer 

solution on, 458; analogy with muscle contraction, 461; as problem in 

colloid-chemistry, 461. 
Cause of oedema, 220, 232; of shock, 415; of nephritis, 474. 
Cellulose, 313. 

Chemical Difference, and distribution, 212. 
Cheyne-Stokes Respiration, 685, 859. 
Chloroform, and nephritis, 499. 
Chlorosis, and oedema, 236. 
Cholecystitis, 828. 
Cholera Red Reaction, 821. 
Chromium, and nephritis, 499. 

Chronic Interstitial Nephritis, 535, 630, 880; interpretations of signs 
associated with, 630; terminal manifestations of, 633; clinical histories of, 
703; treatment of, 717, 719; prognosis in, 751, 886; ambulatory type of, 
880; cardiac type of, 888; cerebral type of, 890. 

Circulation, maintenance of, 403; interference with, and nephritis, 498, 647, 
659. 

Circulatory Disturbances, and oedema, 233; and pulmonary oedema, 
277. 

Citrates, and swelling of gelatin, 586; and " solution " of gelatin, 602; 

and swelling of fibrin, 605. 
Citric Acid, and swelling of gelatin, 586. 
Citrus Fruits, 667. 

Clamping of renal vessels, 647, 659; effect of sodium chlorid on, 659. 

Clasps, dental, 850. 

Classification of the nephritides, 533. 

Clinical Histories, of shock, 417; of nephritis, 696; of chronic interstitial 
nephritis, 703; of glaucoma, 800. 

Cloudy Swelling, in glands, 400; general problem of, 540; theories of, 
540; of kidney, 544; effect of acid on, 544; effect of salts on, 546, 548. 
effect of alkali on, 547; microscopic description of, 548, 553; behavior 
of granules in, 548; as colloid phenomenon, 549, 550, 551; and casein, 
551; interpretation of clouding and swelling, 554; glaucoma as example 
of, 810. 

Coated Tongue, 845. 

Cocain, and oedema, 245; and nephritis, 499. 
Coefficient of distribution, 208. 
Cohesiveness of gluten, 131. 
Cold, and nephritis, 497. 

Colloid-chemical Theory, of water absorption, 204; of oedema, 232, 262; 
of muscle contraction, 461; of albuminuria, 507; of cloudy swelling, 
549, 550, 551; of diapedesis, 557; of urinary secretion,, 337, 349, 640; 
of glaucoma, 796. 



SUBJECT INDEX 



909 



Colloids, definition of, 42, 48; nomenclature of, 42, 44; lyophilic and lyo- 
phobic, 44, 50; emulsion and suspension, 44, 50; hydrophilic and hydro- 
phobic, 44, 50; texts covering, 44; characteristics of, 45, 47; typical, 43; 
classification of, 49; soap, 54; hydration of, 61; hydration of, in liquid 
state, 145; biological importance of, in water absorption, 193; syner- 
esis in, 283; absorption of, from peritoneal cavity, 305, 316, 740; effect 
of, on urinary secretion, 336; intravenous injection of, 405; transfusion 
of, 416; in growth, 447; swelling and solution of, 519; staining of, by 
dyes, 644; reaction of, to indicators, 775. 

Colloid-in-water Systems, reaction of, to indicators, 777. 

Colloid State, 46. 

Coma, 632, 687, 731, 778, 782. 

Consequences, of kidney disease, 614; oedema as one of, of kidney disease, 

626; treatment of, of nephritis, 716, 721. 
Constipation, 313. 

Contraction, of muscle, 451; of catgut, 452; residual, in catgut, 455; 

interpretation of, in catgut, 459. 
Convoluted Tubules, staining of, 484. 

Convulsions, 622, 687, 731; in pregnancy, 659, 728; precipitation of, 754. 
Corneal Opacities, nature of, 806. 
Coronary Disease, 882. 

Corpuscles, swelling of red, 441; loss of color by, 441. 

Correlation, of morphological and clinical manifestations in nephritis, 533. 

Critical Zone, 54. 

Criticism, of osmotic theory of water absorption, 195; of lipoid membrane 
theory of water absorption, 201; of colloid-chemical theory of oedema, 
262; of theories of urinary secretion, 363; of theories of muscle con- 
traction, 463; of solution theory of albuminuria, 530; responses to, 567; 
of case histories of nephritis, 696; of sodium chlorid restriction therapy, 
738; of colloid-chemical theory of nephritis, 769; of colloid-chemical 
theory of glaucoma, 802. 

Crowns, 839; porcelain, 845. 

Crystalloids, 44. 

Curves, of water absorption, 153. 

Cyanids, and nephritis, 499. 

D 

Dakin Solution, 733. 

Dead, tissues, 276; animals, absorption in, 310; muscle, 468; teeth and infec- 
tions, 844. 

Death, and oedema, 240, 244, 289; newer causes of, 817. 
Decapsulation, of kidney, 727, 729. 
Dehydration Therapy, 679, 867. 
Delirium, 731. 
Dental Clasps, 850. 

Dental Procedures, remarks on, 836; pathology of, 837. 
Dentrifices, 841. 
Dentures, partial, 850. 
Devitalized Teeth, 844. 

Dextrose, and fibrin, 70, 71 ; and gelatin, 103, 104, 120; and eye, 177; absorp- 
tion of, from peritoneal cavity, 308; and diuresis, 352; use of, in nephritis, 
713, 730. 

Diabetes, and diuresis, 357. 



910 



SUBJECT INDEX 



Dialysis, 45. 

Dialyzixg Membrane, 45; characteristics of, 45. 

Diapedesis, hemorrhage by, 555; theories of, 555; of white blood cor- 
puscles, 557; colloid-chemical explanation of, 557; model of, 558. 

Dlet, in nephritis, 669; fruit and vegetable, in nephritis, 671; milk, in 
nephritis, 676. 

Diffusion, 318. 

Digitalis, and urinary secretion, 362; in heart disease, 720. 
Dispersoids, 49. 

Dissolved Substances, absorption and secretion of, by protein, 206; peri- 
toneal and alimentary absorption of, 301, 315, 317; secretion of, by 
kidney, 367, 640; secretion of, 393; secretion of, secondary to water- 
secretion, 642. 

Distilled Water, toxic effects of, 402, 434. 

Distribution inequalities, 207; laws, 208; coefficient, 208; and solubility 
208; and adsorption, 210; and chemical differences, 212; importance of, 
in urinary secretion, 641. 

Diuresis, and salts, 339; and sugars, 349; and diabetes, 357: after sweating, 
645. 

Diuretic Salts, see Saline Diuretics. 
Diuretics, of second order, 357, 358, 361. 
Dryness, of skin, 630. 
Duodenal Ulcer, 827. 

Dyes, 210; staining of cells by, 644; in tests of kidney efficiency, 762. 
Dyspnea, 731. 

E 

Eclampsia, see Pregnancy Intoxication. 
Edema, see (Edema. 

Editorials, in Journal of the American Medical Association, 531, 769. 

Efficiency Tests, general principles governing, 755; of kidney, 755. 

Egg-white, absorption of, from peritoneal cavity, 305. 

Emulsoids, 44, 50. 

Endocarditis, 824. 

Entrance Points, for infection, 832. 

Epilepsy, and nephritis, 497. 

Epinephrin, 787. 

Epithelial Cells, 430. 

Equilibrium, 318; osmotic, 320. 

Equimolar Solutions, 65. 

Erythema Nodosum, 825. 

Ether, and urinary secretion, 361, 362; and nephritis, 499. 

Ethylamin, and gelatin, 116. 

Etiology of vascular disease, 634. 

Excretion, see Secretion. 

Explanation, see Interpretation. 

Extraction, methods of, 849; after-treatment of, 849. 

Exudates. 741. 

Eye, absorption of water by, 169; and acid, 170; and alkali, 172; and salts, 
172; and non-electrolytes, 177. 



SUBJECT INDEX 



911 



F 

Fallacy, of sodium chlorid restriction in oedema, 648. 
Fasting, see Starvation. 
Fatalities, in nephritis, 725. 
Fat-like, see Lipoid. 

Feeding, of surgical and medical patients, 788. 
Ferments, proteolytic, and oedema, 242, 245. 
Ferric Chlorid, dialysis of, 371. 
Fever, and oedema, 238. 

Fibrin, swelling of, 61; and carmin, 442; solution of, 508; acid and solu- 
tion of, 510; salts and solution of, 511; staining of, 644; sodium chlorid 
retention by, 736; swelling of, in polybasic acids, 602; swelling of, in 
carbonate mixtures, 604; swelling of, in citrate mixtures, 605; swelling 
of, in phosphate mixtures, 606. 

Filtration, role of, in absorption, 306; of water, 383; theory of urinary 
secretion, 640. 

Filtration Angle, obliteration of, 803. 

Fischer's Solution, see Sodium Carbonate-Sodium Chlorid Solution. 
Flea-bites, 734. 

Focal Infection, 815; and vascular disease, 636, 755, 829; pathology of, 
823; diseases springing from, 824; without localizing symptoms, 828; 
from alveolar abscess, 831. 

Foul Breath, 845. 

Free Water, 306, 333, 382. 

Fruits, citrus, 667; in nephritic diet, 671. 

G 

Gall Stones, 828. 
Gangrene, 241 
Gastric Ulcer, 827. 

Gastro-intestinal Contents, physical chemistry of, 297. 
Gastro-intestinal Tract, absorption from, 311; absorption of water from, 

312; absorption of salt solutions from, 312; absorption of sugars from, 

313; absorption of blood from, 323. 
Gelation, theory of, 527. 
Gelation Capacity, 59. 

Gelatin, swelling of, 75, 519; and urea, 112, 118; and pyridin, 113; and 
amins, 115, 128; and dextrose, 120; liquefaction of, 377, 596; intra- 
venous injection of, 405; solutions for intravenous injection, 416; solu- 
tion of, 513, 519; acid and solution of, 514; salts and solution of, 515; 
swelling of, in polybasic acids, 567; swelling of, in phosphate mixtures, 
568; swelling of, in citrate mixtures, 586; swelling of, in carbonate mix- 
tures, 592; sodium chlorid retention by, 735. 

Gels, change of, to sols, 507. 

Gel State, 59. 

Glands, changes in, during rest and activity, 399; cloudy swelling in, 400. 

Glaucoma, vascular changes as cause of, 632; nature and cause of, 653; 
colloid-chemical theory of, 796; relief of, 797; sodium citrate injections 
in, 798; systemic measures for relief of, 799; nature of corneal opacities 
in, 806; as illustration of cloudy swelling, 810. 

Glomeruli, staining of, 484. 



912 



SUBJECT INDEX 



Gluten, swelling of, 129; cohesiveness of, 131; solution of, 131. 
Gout, 755; infectious nature of, 755. 
Gram-molecular Solution, 66. 

Growth, passive and active, 446; energy for, 447; colloids in, 447; water 

in, 448; osmotic forces in, 448; curvatures, 448. 
Gum-saline Solution, 423. 

H 

Hard Work," and nephritis, 492, 665. 
Hat-fever, 731. 

Heart, l^ertrophy of, 616, 623; failure of, in nephritis, 631; failure of, in 
vascular disease, 720; disease of valves of, 824; disease of muscles of, 825. 

Heart Disease, and nephritis, 496, 854; treatment of, 720; digitalis in, 720; 
alkali and salt in, 720; interpretation of signs and symptoms, 857. 

Heat Coagulation, 148. * 

Hemoglobinuria, paroxysmal, 445, 497, 498. 

Hemolysis, 438; and adsorption, 442; inhibition of, by salt, 658. 

Hemorrhage, effects of, 415; by diapedesis, 555; from kidney, 555. 

Henderson's Respiration Test, 790. 

Herpes Zoster, 825. 

Heterogeneous Systems, 45. 

Histamin, 425. 

Histidin, 268. 

Homogeneous Systems, 45. 

Horse-serum, intravenous injection of, 405, 408, 416. 

Hydration, of fibrin, 61; of gelatin, 75; of gluten, 129; of liquid colloids, 
145; nature of, in proteins, 148; of muscle, 151, 433; of eye, 169; of 
nervous tissue, 178; biological significance of, 203. See also, Absorption 
of Water. 

Hydration Capacity, 59. 

Hydremia, 277, 286, 315. 

Hydrocele Fluid, transfusion of, 416. 

Hydrogen Ion Acidity, of urine, 767. 

Hydrogen Ions, in blood, 477; in urine, 478; estimation of, in. urine, 767. 

Hydrophilic Colloids, 44, 50. 

Hydrophobic Colloids, 44, 50. 

Hypertonic Solutions, absorption of, 319, 435. 

Hypertrophy, of heart, 616, 623. 

Hypotonic Solutions, absorption of, 320, 435. 

Hysteresis, 58, 72. 

I 

Idiopathic (Edema, 670. 

Imbibition, 323, 437. 

Inanition, and oedema, 236. 

Indicators, 52; in urine examinations, 771. 

Indicator Methods, limitations of, 774. 

Indigocarmin, see Sodium Indigosulphonate. 

Infarct, 240. 

Infections, products of, 267; of kidney, 538; of blood stream, 818. 
Injection, rectal, of sodium carbonate-sodium chlorid solution, 681; of 
sodium citrate in glaucoma, 798. See also, Intravenous Injection. 



SUBJECT INDEX 



913 



Injury, brain oedema following, 771. 
Insanity, as brain oedema, 732. 
Insects, stings of, and oedema, 241, 734. 

Interpretation of associated manifestations in nephritis, 629; of experi- 
ments on nephritis, 663; of sodium chlorid retention in nephritis, 734. 
Intestinal Contents, physical chemistry of, 297. 
Intestine, see Gastro-intestinal Tract. 

Intravenous Injection, of salt solution, 404; of blood, 405; of gelatin, 
405, 416; of blood-serum, 408, 416; of casein, 411, 413; of sodium 
carbonate-sodium chlorid solution, 559; of dextrose, 690, 730. 

Iron, solution of, 375. 

Isosmotic, 197. 

Isotonic, 197; solutions, and absorption of, 320, 435. 
Isotonicity, 197. 

J 

Joint Affections, 731, 825.- 

K 

Kaolin, 210 

Kidney, passive congestion of, 268; osmotic behavior of, 275; physical 
chemistry of, 326; secretion of water by, 330; work of, 358; conditions 
affecting output of water by, 357; transition from physiology to path- 
ology in, 365; secretion of dissolved substances by, 368; " solution " of, 
376; staining of, in nephritis, 480; secondarily contracted, 534; small red, 
534; primarily contracted, 535; infections of, 538, 826; small gray, 
539; cloudy swelling in, 544; hemorrhage from, 555; loss of substance in, 
627; decapsulation of, 727, 729; efficiency tests for, 755. 

Kidney Efficiency Tests, 755; general principles governing, 757; strain 
in, 757. 

L 

Lactic Acid and oedema, 235. 

Laws of osmotic pressure, 197; of distribution, 208. 

Lead, and nephritis, 499. 

Lesions, anatomical, of vascular disease, 635. 

Leucocytes, in urine, 750. 

Leukemia, and oedema, 236; and nephritis, 497. 

Levulose, and fibrin, 70, 71; and gelatin, 102, 104; and diuresis, 353. 
Ligation, and oedema, 220; of renal vessels, 269. 

Lipoids, membranes of, 153, 201; and distribution coefficient, 208; and 
solubility, 208. 

Liquefaction, of gelatin in polybasic acids and their salts, 596. 
Liquid Colloids, hydration and dehydration in, 145; viscosity of, 146. 
Liver, passive congestion of, 268; ligation of vessels in, 272; osmotic behav- 
ior of, 276; yellow atrophy of, 630. 
Living tissues, 276; muscle, 468. 
Local (Edemas, 240. 
Loss of kidney substance, 627. 
Lungs, infections of, 826. 

Lymph, role of, in absorption, 301; compared with blood, 302; composition 
of, 302; formation of, 397; salts and formation of, 398; and drugs, 
398; why it remains in the lymph vessels, 403. 

Lymphagogues, 398. 



914 



SUBJECT INDEX 



Lyophilic Colloids. 44. 50. 55: concept of. 60. 
Lyophobic Colloids, 44, 51. 55: concept of. 60. 

M 

Magnesium Sulphate, in oedema, 679. 733: in nephritis, 679; as tissue 

dehvdrant . 731. 
Mania, 632. 
Marasmus, 731. 
Masked Nephritides. 750. 

Memcal Patients, prophylaxis of nephritis in. 7S3: care of, 783; feeding of, 
788. 

Membranes, osmotic. 153, 196: lipoid. 153. 201; precipitation, 196; semi- 
permeable, 196. 
Mercury Drop, and diapedesis, 55S. 
Metal Proteinates. 526. 
Methyl Orange. 771. 
Methyl Red. 771. S61. 
Micro-capillary Structure. 383. 
Milk Diet, in nephritis. 076. 

Mineral Water, in oedema. 237: in nephritis. 673. 

Model, first, of urinary secretion. 327: second, of urinary secretion. 371; 
third, of urinary secretion. 350: of growth curvature. 450' of diapedesis, 
558. 

Molar Solutions. 65. 
Molecular Size. 47. 
Molecular Solutions. 66. 
Molecules. 47. 

Morphin. 757: and oedema. 245: and urinary secretion, 361; and lymph for- 
mation. 398; and nephritis. 499. 

Morphological Changes, in nephritis. 532-: and clinical manifestations 
of nephritis, 533: catalogue of. in kidney in nephritis. 539. 

Mosaic Theory, of Nathansohn. 203. 

Mouth, infection and systemic disease, 815; flora of, and bad breath, 845; 

washes, 849. 
Mucous Colitis, 731. 

Muscle, swelling of. 151. 433; osmotic properties of. 152: and acid, 154; 
and alkali, 156; and salts, 160; and non-electrolytes, 164; contraction 
of. 451: analogy between contraction of. and catgut. 461: historical and 
critical remarks on contraction of, 463; role of acid in contraction of, 
466: living and dead, 465. 

N 

Nephrectomy, 627. 

Nephritis, and oedema, 238; and pulmonary oedema, 279: definition of, 
473: common cause for, 474: thesis of. 474; abnormal production and 
accumulation of acid in. 475: urine in, 478: decreased alkalinity of 
blood in. 479: and staining of kidney. 480; and ammonia excretion, 
487; low carbonic acid content of blood in, 487; abnormal acids in, 
4S7: blood colloids in. 458; tolerance to alkali in, 488; after acid in- 
jection, 489; of hard work, 492, 665; of athletes, 493; in heart disease, 
496: in respiratory disease, 496: in anemia. 497; in carbon monoxid 
poisoning. 497: in epilepsy, 497: in leukemia, 497; after exposure to 
cold. 497: after direct interference with kidney circulation, 498; in 



SUBJECT INDEX 



915 



vascular disease, 499; consequent upon drugs, 499; consequent upon 
anesthetics, 499; consequent upon poisons, 499; of the newborn, 500; 
of salt starvation, 501; after excessive water consumption, 501; of 
other than acid causes, 502; due to alkali, 502; morphological changes 
in, 532; classification of types of, 533; parenchymatous, 533; correla- 
tion of morphological and clinical manifestations in, 533; chronic inter- 
stitial, 534; hemorrhage in, 555; alleged consequences of, 614; relation 
of, to vascular disease, 614; and oedema, 626, 664; and uremia, 628; 
reintefpretation of associated manifestations, 629; disturbances of 
secretion in, 636; secretion of water in 638; secretion of dissolved 
substances in. 640; experimental foundations for treatment of, 648; 
asphyxial, 649; and Ringer solution, 652; relief of, by sodium chlorid, 
655; following clamping of renal vessels and relief of, by sodium chlorid, 
659; interpretation of experiments on, 663; treatment of patients with, 
667; use of alkali in, 668; use of salts in, 668; use of dextrose in, 668; 
general rules for treatment of, 668; diet in, 669; acids and treatment 
of, 669; water consumption in, 674; role of salts in, 676; milk diet in, 
676; physiological salt solution in, 677; more aggressive treatment of, 
680; bivalent metals in, ,685; treatment of severe cases of, 686; treat- 
ment of alleged consequences of, 686, 721; toxic types of, 699; after 
phosphorus and metallic poisoning, 701; treatment of, due to preg- 
nancy intoxication, 704; treatment of chronic interstitial, 717; use of 
alkali in chronic interstitial, 718; clinical histories of fatalities in, 725; 
diagnosis and prognosis in, 746; significance of casts in, 748; and heart 
failure, 749; high blood pressure in, 752; brain oedema in, 752; kidney 
efficiency tests in, 755; acidity measurement of urine in, 765; ammonia 
determinations in, 780; acetone bodies in, 781; uremia of, 782; pro- 
phylaxis of, 783; and infection, 826; clinical lecture on, 852; and heart 
disease, 854; of general intoxication, 863; of pregnancy, 863; infectious, 
876; spotty parenchymatous, 876; chronic interstitial, 880. 
Nerve Blocking, 788. 

Nerves, vasomotor and secretory, 397, 398, 399^ 400. 

Nervous Tissue, swelling of, 178; and acids, 180; and salts, 181; and 

non-electrolytes, 188. 
Neutral Red, 645. 

Non-acid Causes of oedema, 262; of nephritis, 502. 

Non-electrolytes, and fibrin, 69; and gelatin, 93, 99, 100; and aleuronat, 
139; and muscle, 164, 436; and eye, 177; and nervous tissue, 188; and 
oedema, 258; absorption of, from peritoneal cavity, 308. 

Normal Solutions, 66. 

O 

Oat Diet, 673. 

(Edema, problem of, 41; main discussion of, 217; osmotic theory of, 219; 
ligation experiments on, 220; cause of, resides in tissues, 220; nature 
and cause of, 232; colloid-chemical theory of, 232; abnormal acid ac- 
cumulation in, 232, 233; and circulatory disturbances, 233; and 
lactic acid, 235; in pernicious anemia, 236; in leukemia, 233; in chloro- 
sis, 236;' in inanition, 236; and alkalinity of blood, 236; in starvation, 
237; in fever, 238; of nephritis, 238; of the dead, 240, 244; local, 240; 
of insect stings, 241; and proteolytic ferments, 242, 265; and poisons, 
245; relief of, 249, 260, 738; and salts, 253; and non-electrolytes, 258; 
and sodium chlorid, 262; of non-acid origin, 262; due to alkali, 266; 



916 



SUBJECT INDEX 



due to pyridin, urea and amins, 266; blood pressure theory of, 271; 
of lungs, 276; and syneresis, 283; and transudates, 283; and serous 
accumulations, 283; of cachexia, 287; of nephritis, 626, 664; and 
uremia, 629; fallacy of salt restriction in, 648; reduction of, by sodium 
chlorid, 658; idiopathic, 670; of the brain, in sulphuric acid poisoning, 
721; treatment of, with sodium carbonate-sodium chlorid solution 
731; angioneurotic, 731; as alleged consequence of sodium chlorid 
retention, 734; in absence of circulation, 852. 

Opacities, corneal, 806. 

Optic Nerve, oedema of, 629. 

Oranges, 666. 

Orthostatic Albuminuria, 748. 

Osmotic, properties of muscle, 152; membranes, 153, 196; theory of absorp- 
tion, 275, 276; cells, 196; theory of oedema, 219; behavior of kidney, 
275; behavior of liver, 276; equilibrium, 320; forces in growth, 448. 

Osmotic Pressure, laws of, 197. 

Oxalic Acid, formation of, in plants, 451. 

Oxygen, lack of, and oedema, 234; consequences of lack of, 235; lack of, 
induced chemically, 248; supply and secretion, 360. 

P 

Paranitrophenol, 771. 

Parenchymatous Nephritis, 876; generalized, 533; spotty, 533; oedema of , 
627. 

Paroxysmal Hemoglobinuria, 445, 497, 498. 
Partial Dentures, 850. 
Partition, see Distribution. 

Passive Congestion, of kidney, 268; of liver, 268; explanation of, on 

colloid-chemical basis, 268. 
Peritoneal Cavity, absorption of water from, 299, 303; absorption of 

dissolved substances from, 301 ; absorption of blood from, 305, 740; 

absorption of colloids from 305; absorption of salt solutions from, 306; 

absorption of non-electrolytes from, 308; absorption of acid and alkali 

from, 309; secretion of fluid into, 742. 
Peritoneum, see Peritoneal Cavity. 
Pernicious Anemia, 236, 497. 
Phases, 45; internal and external, 58. 
Phenol/Water, 52, 53. 
Phenolphthalein, 52, 771. 

Phenolsulphonephthalein, in alkali therapy, 672; as kidney test, 762. 
Phosphate Mixtures, 377; and swelling of gelatin, 568; and " solution " of 

gelatin, 597; and swelling of fibrin, 606. 
Phosphorus, and nephritis, 499, 701. 

Physiological theory of absorption, 317, 321; driving force, 321. 
Physiological Salt Solution, 66, 435; in nephritis, 677; perfusion of 

kidneys with, 729. 
Physiologische Triebkraft, 321. 
Physostygmin, and lymph formation, 398. 
Pilocarpin, and lymph formation, 398. 
Plague, 820. 

Plants, proteins in, 145; growth curvatures in, 448; growth in, 448; pro- 
tection against water loss in, 450; formation of oxalic acid in, 451. 
Plasmolysis, 429. 



SUBJECT INDEX 



917 



PLASMOPTYSIS, 429. 

Plethora, 285. 

Pneumococcus Infection, 819. 
Points, of entrance for infection, 832. 

Pol yb asic Acids, swelling of gelatin in, 567; liquefaction of gelatin in, 596; 

swelling of fibrin in, 602. 
Polyuria Tests, 760. 

Postoperative Treatment of surgical patients, 788. 
Precipitation Membranes, 196. 

Pregnancy Intoxication, theory of, 704; clinical manifestations of, 704 
treatment of, 704; convulsive seizures in, 728; and nephritis, 863; prog- 
nosis of, 874. 

Pre-operative Care, 783. 

Preparation of sodium carbonate-sodium chlorid solution for rectal use, 
681; of sodium carbonate-sodium chlorid solution for intravenous 
use, 686; of surgical patients, 783. 

Pressure Bottle, 691. 

Pressure Theory, of oedema, 218; of secretion, 359; of urinary secretion, 639. 
Primarily Contracted Kidney, 535. 
Prognosis, in nephritis, 746; in uremia, 765. 
Prophylaxis, of nephritis, 783. 

Protein, 51; swelling of, 61; plant, 145; nature of hydration and dehydration 
of, 148; as fatty acid analog, 148; salts of, 149; amphoteric, 150; analogy 
of, with protoplasm, 151; solution of, 507, 519; swelling of, 519; in 
nephritic diet, 670; reaction of, to indicators, 775. 

Protein/ Water, 52, 53. 

Proteolytic Ferments, and oedema, 242, 265. 
Proteus Vulgaris, 267. 

Protoplasm, analogy of, with protein swelling, 151; absorption and secre- 
tion of dissolved substances by, 206. 
Protoplasm/ Water, 52. 

Pulmonary (Edema, 276; due to circulatory disturbances, 277; due to 
acid, 279; in nephritis, 279; in vascular disease, 279; in excised lungs, 
280. 

Putrefaction, 267, 268. 

Pyorrhea, 842, 846; signs of, 846; treatment of, 847; scaling in, 847. 
Pyridin, 122, 123; and fibrin, 73; and gelatin, 113, 114, 115; and oedema, 266. 

Q 

Quantitative Aspects, of water absorption in muscle, 168; of water absorp- 
tion in gastro-intestinal tract, 314. 

QUELLUNGSWASSER, 437. 

R 

Reaction, after intravenous injections, 694. 

Rectal Injection, of sodium carbonate-sodium chlorid solution, 681 ; amount 

of, 684. 
Relief, of oedema, 249, 260. 

See also, Treatment. 
Removal of kidney substance, 627. 
Respiration, in acidosis, 790. 
Respiratory Disease, and nephritis, 496. 
Retention, of water, 333; of sodium chlorid and oedema, 734. 



918 



SUBJECT INDEX 



Retinitis, albuminuric, 631. 

Reversibility, of water absorption in fibrin, 71; of water absorption in 
gelatin, 109; of water absorption in muscle, 165; of water absorption 
in eye, 177; of water absorption in nervous tissue, 190; of changes in 
nephritis, 553. 

Rheumatism, 827. 

Rigor, 463, 465, 470. 

Rigor Mortis, 470. 

Ringer Solution, and catgut, 458; in treatment of nephritis, 652. 
Root Canal Fillings, 844. 

S 

Saccharose, and fibrin, 70, 71, 74; and gelatin, 100, 104; and muscle, 166; 
and eye, 177; absorption of, from peritoneal cavity, 308; and diuresis, 
355. 

Saline Cathartics, 313, 324. 
Saline Diuretics, 339, 389; mode of action, 339. 
Salines, effect of, on blood pressure, 409. 
Saliva, reaction of, 774. 

Salivary Glands, changes in, during rest and activity, 399. 
Salt Solutions, fate of, after intravenous injection, 404. 
Salting-out, 54. 

Salts, and fibrin, 65; and gelatin, 81; and aleuronat, 139; of proteins, 149; 
effects of, 151; and muscle, 160; and eye, 172; and nervous tissue, 181; 
and oedema, 253; absorption of, from peritoneal cavity, 306; diuretic, 
339; and lymph formation, 398; and catgut, 456; and solution of fibrin, 
511; and solution of gelatin, 515; and swelling of gelatin, 525, 567; 
and "solution" of gelatin, 525, 596; and cloudy swelling, 546, 548; 
and swelling of fibrin, 602; use of, in nephritis, 668, 676; starvation in 
nephritis, 677. 

Salvarsan,, 731; cedema-producing effects of, 789; avoidance of after 

effects from, 789. 
Scaling of Teeth, 847. 
Scarlet Fever, and nephritis, 700, 701. 
Scopolamin, 787. 
Scurvy, 731. 
Seaweed, 314. 

Secondarily Contracted Kidney, 534. 

Second Order of diuretics, 358, 361. 

Secreting System, 326; physical chemistry of, 326. 

Secretion, general problem of, 293, 325; of water by kidney, 330; surface 
tension theory of, 349; influence of circulation on, 359; blood pressure 
theory of, 359; and oxygen supply, 360; of dissolved substances by 
kidney, 368; as filtration process, 383; differential, 393; disturbances of, 
in nephritis, 636; of water in nephritis, 638; of dissolved substances in 
nephritis, 640, 642; into cavities, 283, 742. See also, Urinary Secretion. 

Secretory, theory of absorption, 321; work of kidney, 358; nerves, 397, 400. 

Selective, absorption, 319; secretion bv kidney, 370. 

Semipermeable Membranes, 196. 

Sequestra, 839. 

Serous Cavities, fluid accumulations in, 285. 
Serum, see Blood and Blood Serum. 



SUBJECT INDEX 



919 



Shock, cause of, 415; cases of, 417; principles of treatment in, 422; critical 
remarks on, 423; transfusion mixtures in, 424; palliative measures in, 
425; amins and, 425 ; peptone, 425; wound, 425; histamin, 425; oxygen 
and, 425; carbohydrates in, 426; toxemic, 728; surgical, 787; protection 
against, 787. 

Skin Affections, 825. 

Small Gray Kidney, 539, 631. 

Small Red Kidney, 534, 631. 

Soap Cups, 383. 

Soaps, 51; solvated, 58; of different bases, 396; reaction of, to indicators, 775. 
soap-in-water, 52, 56. 
Soap/Water, 52. 

Sodium Bicarbonate, in oedema, 679; in nephritis, 679. 

Sodium Carbonate, 680; equivalents of different kinds, 6$1. 

Sodium Carbonate-sodium Chlorid Solution, preparation of, 680; rectal 
injection of, 681; amount of, to be injected, 683; preparation of, for 
intravenous use, 686; intravenous injection of, 690; quantity and 
time interval for intravenous injection, 692; reaction following use of, 
694; as general treatment for oedema, 731; use of, in acute infections, 
731. 

Sodium Chlorid, and oedema, 262, 658; effects of, on urinary secretion, 
331, 653; and water retention, 333; starvation and nephritis, 501; 
restriction of, in nephritis, 648, 734; relief of asphyxial nephritis by, 
649 ; effects of, on urinary secretion in nephritis, 653 ; reduction of oedema 
by, 658; inhibition of hemolysis by, 658. 

Sodium Chlorid Retention, 734. 

Sodium Chlorid-Sodium Citrate Solution, 731. 

Sodium Citrate, injections of, in glaucoma, 798. 

Sodium Indigosulphonate, staining of kidneys by, 483, 645. 

Sodium Oleate, 51. 

Sodium Stearate, 51. 

Sol State, 59. 

Solubility, and distribution, 208. 

Solution, definition of, 51; of gluten, 131; of protein, 507; of fibrin, 508; of 

gelatin, 513; relation of, to swelling, 519; of gelatin in polybasic acid^ 

and their salts, 596. 
Solution, Fischer's, see Sodium Carbonate-Sodium Chlorid Solution. 
Solutions, molar, gram-molecular, and molecular, 65, 66; normal, 66; 

physiological, 66, 435; absorption of colloid, 305, 316; effect of colloid, 

on urinary secretion, 336. 
Solution Theory, of albuminuria, 506. 
Solvation Capacity, 59. 
Spasm, of blood vessels, 881. 
Spermatozoa, absorption of water by, 430. 
Spirochete, of syphilis and vascular disease, 636. 
Spring Water, see Mineral Water. 
Staphylococci, and vascular disease, 636. 
Staphylococcus Pyogenes Aureus, 267. 

Starvation, and oedema, 237; salt, and nephritis, 501, 667; acidosis, 672. 
Stomata, 555. 
Strain Tests, 757. 

Streptococcus, and vascular disease, 636; infections, 820; types of, 822. 
Strychnin, and oedema, 245; and nephritis, 499. 



920 



SUBJECT INDEX 



Stupor, 632, 687, 731. 

Sugars, and fibrin, 71; and gelatin, 93; and muscle, 165; and eye, 177; 
absorption of, from peritoneal cavity, 308; absorption of, from gastro- 
intestinal tract, 313; diuretic action of, 349; use of, in treatment of 
nephritis, 730. 

Sugar Diuresis, 349. . 

Suprarenin, 787. 

Surface Tension Theory of secretion, 349. 

Surgical Patients, preparation of, 783; acid intoxication in, 785; post- 
operative treatment of, 788. 
Suspensoids, 44,50. 
Sweat, 59. 

Sweating, effects of, 685. 

Swelling, of fibrin, 61; of gelatin, 75; similarities and differences in, of fibrin 
and gelatin, 123; of gluten, 129; of aleuronat, 133; of muscle, 155, 433; 
of eye, 169; of nervous tissue, 178; relation of, to solution, 519; cloudy, 
540; of gelatin in polybasic acids, 567; of gelatin in phosphate mixtures, 
568; of gelatin in citrate mixtures, 586; of gelatin in carbonate mixtures, 
592; of fibrin in polybasic acids, 602. 

Swelling Capacity, 59. 

Syneresis, 59, 283. 

Systemic Disease, and mouth infection, 815. 
Systems, homogeneous and heterogeneous, 45. 

T 

Tartaric Acid, and nephritis, 673. 

Teeth, 837; devitalization of, 839; care of, 840; brushing of, 841; use of, 841; 

cleaning of, 842; reconstruction of, 843; devitalized, 844; scaling of, 847. 
Testicle, 531. 

Tests, efficiency, of kidney, 755; strain, 757. 

Theory, osmotic, 195; lipoid, 201; mosaic, 203; colloid-chemical, 204; 
of oedema, 217; increased permeability, of oedema, 219; colloid-chemical, 
of oedema, 232; blood pressure, of oedema, 271; of absorption, 315; 
filtration, of absorption, 316; osmotic, of absorption, 317; physiological 
secretory and vitalistic, of absorption, 317, 321; surface tension, of 
secretion, 349; blood pressure, of secretion, 359; of urinary secretion, 
and criticism thereof, 363; of muscle contraction, 463; of albuminuria, 
505; solution of albuminuria, 506, 517; of gelation, 527; of cloudy swelling 
540; of diapedesis, 555; colloid-chemical, of diapedesis, 557; of urinary 
secretion, 640; colloid-chemical, of urinary secretion, 640; of pregnancy 
intoxication, 704; colloid-chemical, of glaucoma, 704. 

Therapy, See Treatment. 

Thoracic Duct, peritoneal absorption after ligation of, 302. 

Thymolphthalein, 771. 

Thyroid Disease, 826. 

Tissue Localization, 820. 

Tissue Spaces, 285. 

Titration Acidity, of urine, 766. 

Toluidin Blue, 644. 

Tooth Brushes, 841. 

Tongue, coated, 845. 

Toxemic Shock. 728. 

Toxic, effects of distilled water, 402, 434; types of nephritides, 699, 702. 



SUBJECT INDEX 



921 



Transfusion, of blood, 416; of hydrocele fluid, 416; of ascitic fluid, 416; of 

colloid solutions, 416. 
Transition, from physiology to pathology of kidney, 366. 
Transudation, 283, 738. 
Trauma, see Injury. 

Treatment, of oedema, 249, 260, 679, 738; of low blood pressure, 415"; of 
nephritis, 648, 679; more aggressive, of nephritis, 680; of nephritis with 
bivalent metals, 684; of severe cases of nephritis, 686; of pregnancy 
intoxications, 704; of chronic interstitial nephritis, 717; explanation 
of good results following sodium chlorid restriction, 742; of high blood 
pressure, 753; postoperative, 788; of glaucoma, 797. 

Tropisms, 448. 

True Solution, 46. 

Tubercle Bacillus, variation in, 821. 

Turgor, 196, 429. 

Twitching, 731. 

U 

Ulcer, gastric, 827; duodenal, 827. 

Uranium, and cedema, 245; and nephritis, 499. 

Urea, and fibrin, 73; and gelatin, 112, 113, 114, 118; and muscle, 164; and 

eye, 177; and nervous tissue, 188; and oedema, 266; absorption of , from 

peritoneal cavity, 308. 
Uremia, 628, 632; not secondary to kidney loss, 628; as a brain oedema, 

629; periodic character of, 633; without urinary findings, 750; prognosis 

in, 765; and nephritis, 782. 
Urinalysis, significance of, 746. 

Urinary Secretion, model of, 327; conditions for, 330; effect of sodium 
chlorid on, 331, 653; effect of blood injections" on, 336; effect of colloid 
solutions on, 336; blood pressure theory of, 359; effect of drugs on, 
361, 362; critical remarks on, 363; theories of, 639; pressure theory 
of, 640; colloid-chemical theory of, 640; effect of sodium chlorid on, 
in nephritis, 653. 

Urine, physical chemistry of, 326; in nephritis, 478; acidity of normal, 
478, 861; acidity of abnormal, 478, 861; acidity measurements of, 765; 
titration acidity of, 766; hydrogen ion acidity of, 767; use of indicators 
in examination of, 771. 

Urticaria, 241, 267, 734. 

V 

Valvular Heart Disease, 824. 
Varicose Veins, 635. 

Vascular Disease, and pulmonary oedema, 279; and nephritis, 499, 719; 
rc-rays of, in kidney, 537; definition of, 537; relation of, to nephritis, 
614; relation of heart hypertrophy to, 616, 623; etiology of, 634; para- 
sitic origin of, 635; anatomical lesions of, 635; varicose veins in, 635; 
heart failure in, 720; labored breathing in, 731; foci of infection in, 755, 
830: and syphilis, 831; nephritis in, 880; and increased blood pressure, 
884. 

Vasomotor Nerves, 397, 398, 399. 
Vegetables, in nephritic diet, 671. 
Velocity, of blood and secretion, 360. 
Viscosity, of liquid colloids, 146; of blood, 625, 
Vitalistic Theory of absorption, 317. 



922 



SUBJECT INDEX 



W 

Water, of condensation, 283; free, 306; retention, 333; in growth, 448; 

loss of, in plants, 450; excessive consumption of, and nephritis, 501; 

consumption of, in nephritis, 674; advantages of, in nephritis, 674; 

objections to, in nephritis, 675. 
Water Absorption, by fibrin, 61, 71; by gelatin, 75; by gluten, 129; by 

muscle, 151, 433; by eye, 169; by nervous tissue, 178; osmotic theory 

of, 195; from peritoneal cavity, 300, 303; from gastro-intestinal tract, 

313; by spermatozoa, 430; by epithelial cells, 430; by white blood 

corpuscles, 430. 
Water-in-colloid Systems, reaction of, to indicators, 777. 
Water-in-soap, 51. 
Water/Phenol, 52, 53. 
Water/Protein, 52. 
Water/Protoplasm, 52. 

Water Secretion, by kidney, 330; mechanism of, by kidney, 357; condi- 
tions affecting, 358; in nephritis, 638; model of, 380; effect of sodium 
chlorid on, in nephritis, 653. See also Secretion. 

Water/Soap, 52, 56. 

Wet Dressings, 731. 

Wheals, 241. 

Work, of kidney, 358, 640; demands on heart, 623. 



X 

X-rays of vascular disease in kidney, 536. 




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CIVIL ENGINEERING — Continued 
5e Highways; Municipal Engineering; Sanitary Engineering; 
Water Supply. Forestry. Horticulture, Botany and 
Landscape Gardening. 



6 — Design. Decoration. Drawing: General; Descriptive 

Geometry; Kinematics; Mechanical. 

ELECTRICAL ENGINEERING— PHYSICS 

7 — General and Unclassified; Batteries; Central Station Practice; 
Distribution and Transmission; Dynamo-Electro Machinery; 
Electro-Chemistry and Metallurgy; Measuring Instruments 
and Miscellaneous Apparatus. 



8 — Astronomy. Meteorology. Explosives. Marine and 
Naval Engineering. Military. Miscellaneous Books. 

MATHEMATICS 

9 — General; Algebra; Analytic and Plane Geometry; Calculus; 
Trigonometry; Vector Analysis. 

MECHANICAL ENGINEERING 

10a General and Unclassified; Foundry Practice; Shop Practice. 
10b Gas Power and Internal Combustion Engines; Heating and 

Ventilation; Refrigeration. 
10c Machine Design and Mechanism; Power Transmission; Steam 

Power and Power Plants; Thermodynamics and Heat Power. 

1 1 — Mechanics. 

12 — Medicine. Pharmacy. Medical and Pharmaceutical Chem- 
istry. Sanitary Science and Engineering. Bacteriology and 
Biology. 

MINING ENGINEERING 

13 — General; Assaying; Excavation, Earthwork, Tunneling, Etc.; 
Explosives; Geology; Metallurgy; Mineralogy; Prospecting; 
Ventilation. 



14— Food and Water. Sanitation. Landscape Gardening. 
Design and Decoration. Housing, House Painting. 




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